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Item 1. Business

2022-03-17 compared with 2021-03-16 · 252 added, 802 removed, 552 unchanged (66% of the section changed)

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 are a clinical-stage fully integrated oncology company built on a foundation of drug discovery excellence to deliver novel precision cancer medicines to underserved patients.

We believe our approach could result in better targeted cancer therapies.

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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.

Food and Drug Administration, or the FDA, for six investigational new drug applications, or INDs, and successfully advanced these programs into clinical trials.

In addition, we have two unique programs in various stages of preclinical development that we plan to advance into clinical development in 2022.

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 following table summarizes our product candidate pipeline:

Our most advanced 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.

PRT543, our first clinical candidate, is currently in a Phase 1 clinical trial in advanced solid tumors and select myeloid malignancies.

As of an August 6, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT543 enrolled a total of 49 patients across 18 unselected advanced solid tumors and lymphoma.

Patients enrolled in the trial received an average of three prior lines of therapy.

PRT543 demonstrated target engagement and inhibition of PRMT5 functional activity as evidenced by a 69% reduction in serum symmetric dimethylarginine, or sDMA, at a dose of 45 mg/5x per week.

In addition, PRT543 demonstrated signs of preliminary clinical activity, including a durable complete response, or CR, maintained for over 18 months in a patient with HRD+ ovarian cancer who remains on treatment, and prolonged stable disease, or SD, persisting for over six months in five patients, including four patients with ACC and one patient with uveal melanoma.

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

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.

PRT543 was generally well tolerated:

the most common grade 3 or higher treatment-related adverse events, or AEs, occurring in at least 5% of patients were thrombocytopenia (27%) and anemia (12%), both of which were reversible upon treatment interruption.

Patients were largely able to remain on therapy with few AE-related dose interruptions (27%), reductions (22%), or discontinuations (4%).

Patient enrollment is continuing in specific biomarker-selected solid tumor and hematologic malignancy expansion cohorts.

We anticipate presenting data from those expansion cohorts in the second half of 2022.

PRT811, our second clinical candidate, is a PRMT5 inhibitor that we have optimized for high brain exposure.

PRT811 is being studied in a Phase 1 clinical trial in unselected patients with solid tumors, including high-grade glioma.

As of an August 13, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT811 enrolled a total of 45 patients, including 27 patients across 16 unselected advanced solid tumors and 18 patients with high-grade gliomas, including 17 patients with glioblastoma multiforme.

PRT811 demonstrated dose dependent inhibition of PRMT5 activity as evidenced by an 83% reduction in serum sDMA at a dose of 600 mg daily (QD).

In addition, PRT811 demonstrated signs of preliminary clinical activity, including an IDH1 mutated high-grade glioma (glioblastoma (GBM)) patient who experienced a partial response, or PR, that evolved into a durable CR for more than 13 months.

In addition, a patient with splicing-mutant, or SF3B1, uveal melanoma demonstrated SD for more than six months with a 25% tumor regression.

At a post data-cutoff on September 20, 2021, one additional patient (receiving a dose of 800 mg QD) with SF3B1 uveal melanoma had an unconfirmed PR and 47% decrease in target lesion, and a patient with triple negative breast cancer (receiving a dose of 800 mg QD) demonstrated a 27% decrease in target lesions.

PRT811 was generally well-tolerated;

the most common grade 3 or higher treatment-related AE was thrombocytopenia (7%), which was reversible upon treatment interruption.

Patients were largely able to remain on therapy with few AE-related dose interruptions (13%), reductions (4%), or discontinuations (3%).

On March 9, 2022, we announced that we are concentrating our further development efforts on PRT811 in biomarker-selected patients in specific cancer types.

While the Company believes that both PRT811 and PRT543 are high quality,

clinically active compounds, PRT811 was selected based on its superior safety profile, higher level of target engagement, and unique brain penetrant properties.

Specifically, we intend to:

Focus clinical development in select patient populations where clinical activity has been observed, including splicing mutated myeloid malignancies and solid tumors including uveal melanoma and IDH1 mutated high grade gliomas.

Complete data analysis of the ongoing expansion cohort of adenoid cystic carcinoma (ACC) by mid-year to determine further development.

Report data from the ongoing dose expansion cohorts in the second half of 2022.

Determine appropriate development options for PRT811 based on emerging data from ongoing expansion cohorts.

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1.

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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:

The dose escalation portion of the Phase 1 trial of both oral formulation and the intravenous, IV, formulation, which leverages the optimized physicochemical properties of PRT1419, are underway in patients with solid tumors and hematologic malignancies.

On March 9, 2022, we announced that we are prioritizing development of the IV formulation of PRT1419, which demonstrated a desirable pharmacokinetic, pharmacodynamic and safety profile with potential for differentiation from competitor compounds.

We intend to initiate a combination trial with venetoclax by mid-year with the goal of establishing safety, clinical activity and a recommended Phase 2 dose in the second half of 2022.

PRT2527, our fourth clinical candidate, is designed to be a potent and selective Cyclin-dependent kinase 9, or CDK9, inhibitor.

In preclinical studies, PRT2527 was shown to reduce MCL1 and MYC protein levels and was highly active in preclinical models at well-tolerated doses.

PRT2527 has demonstrated high potency and kinase selectivity which may offer improved efficacy and safety compared to less selective CDK9 inhibitors.

Preclinical data demonstrated that treatment with PRT2527 depleted oncogenic drivers with short half-lives, such as MYC and MCL1, and effectively induced apoptosis.

PRT2527 treatment demonstrated robust efficacy in both hematological malignancies and solid tumor models with MYC dysregulation.

A phase one trial is underway evaluating escalating IV doses of PRT2527 as a monotherapy in patients with selected solid tumors, including sarcoma, prostate cancer, lung cancer, and other cancers with genomic alterations that lead to MYC dependence.

On March 9, 2022, we announced that we intend to complete enrollment in the Phase 1 dose escalation study of PRT2527 with the goal of identifying a recommended Phase 2 dose in the second half of 2022.

In addition to our four clinical stage candidates, we are advancing two new preclinical programs.

Our most advanced preclinical program has led to the identification of PRT3645, a brain penetrant molecule that potently and selectively targets CDK4/6.

IND-enabling studies for PRT3645 are ongoing and we plan to complete IND-enabling studies, file an IND and initiate a Phase 1 clinical trial in the second half of 2022.

Our second pre-clinical program targets Brahma homologue, or BRM, otherwise known as SMARCA2.

We have identified SMARCA2 protein degraders that demonstrate selective degradation of SMARCA2 at sub-nanomolar concentrations.

We are currently profiling our lead compound, PRT-SCA2, and plan to submit an IND application by year-end 2022.

Prelude Discovery and Development Approach

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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 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

have established an expansion dose.

We expect these expansions to begin by mid- 2021 and anticipate initial clinical results from th is 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.

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.

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:

Rapidly progress our lead product candidates, PRT543 and PRT811, through clinical development in patients with select solid tumors and hematological malignancies.

Our oral PRMT5 inhibitor candidates target multiple indications, with an initial focus on ACC, HRD+ tumors, myeloid and CNS malignancies, and have the potential for accelerated approval.

We are currently advancing our first clinical candidate, PRT543, in a Phase 1 clinical trial in select solid tumors and myeloid malignancies.

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 durable confirmed CR in a highly-refractory HRD+ ovarian cancer patient and prolonged stable disease, or SD, defined as failure to meet the definitions of either objective clinical response or progressive disease, in multiple patients with myeloid malignancies.

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.

The previously disclosed refractory GBM patient whose tumor had demonstrated a 66% reduction on monotherapy PRT811 has subsequently undergone 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.

We have recently completed the dose escalation portion of the ongoing Phase 1 trial for PRT543.

Patient enrollment into the expansion portion of the trial for PRT811 is expected to begin by mid-2021.

anticipate presenting initial clinical results for PRT543 in the second half of 2021 and obtaining initial clinical results for PRT811 by the end of 2021.

Expeditiously advance PRT1419, our MCL1 inhibitor, through clinical development in patients with select hematological malignancies.

MCL1 is an oncogenic driver and a major resistance mechanism to B-cell lymphoma 2, or BCL2, inhibitors.

We are enrolling patients into the dose escalation portion of a Phase 1 clinical trial investigating oral PRT1419 in high risk MDS, AML, NHL and MM patient s .

We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial for the oral formulation of PRT1419 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.

Continue to advance our earlier stage programs, including a CDK9 inhibitor and a SMARCA2 degrader.

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 potent SMARCA2 protein degraders based on 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.

Leverage our cancer biology and medicinal chemistry expertise to consistently deliver one new IND every 12 – 18 months.

We are committed to developing drugs that take a unique approach to precision oncology by focusing on broad mechanisms that have multiple links to oncogenic driver pathways in select patients.

Utilizing our unique fully-integrated targeted oncology discovery engine, we will continue to pursue small-molecule therapies optimized to effectively target the key driver mechanisms in cancers with high unmet need, regardless of target class or technology platform.

Since our inception in 2016, we have received FDA clearance for four INDs and successfully advanced three of these programs into clinical development, with the fourth program expected to initiate clinical development in the first half of 2021.

We aim to continue to deliver on our goal of creating better targeted and more effective cancer therapies for patients with high unmet need.

Opportunistically evaluate strategies to accelerate development timelines and maximize the value of our product candidate pipeline.

We have developed each of our product candidates based on our internal capabilities, and we currently have worldwide development and commercial rights to each of our candidates.

Given our ability to efficiently invent target class agnostic, small molecule agents that have broad applicability, including potential indications beyond oncology, we may choose to opportunistically enter into strategic collaborations that enable us to broaden our clinical or commercial impact.

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.

We intend to become a fully integrated oncology company on the foundation of drug discovery excellence to deliver novel precision oncology medicines to patients with underserved cancers by pursuing the following objectives:

Leverage our cancer biology and medicinal chemistry expertise to strive to deliver one new IND every 12 – 18 months.

Discover and develop differentiated small molecules NCEs in validated targets that address unmet needs of oncology patients.

Rapidly progress our product candidates through clinical development in patients with solid tumors and hematological malignancies.

Focused clinical development in underserved cancers, and design clinical trials for allowing efficient decisions with the highest probability of success and potential for rapid regulatory approval.

Advance our product candidate pipeline in combination with internally discovered and third-party developed compounds.

Evaluate strategic opportunities to accelerate development timelines and maximize the value of our product candidates.

Cancer Background and Treatment

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These precision medicines are broadly known as targeted therapie s .

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

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.

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.

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:

Transcriptional regulation

DNA repair pathway

Cell cycle regulation

Exploitation of synthetic lethality

Brain penetrant molecules to address primary or metastatic CNS tumors

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.

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.

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

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Spliceosomal protein s —large protein complex that removes introns from pre-mRNA to yield mature

PRMT5 Regulates Oncogenesis and Resistance

PRMT5 Pathway Drives 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.

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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.

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.

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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.

PRMT5 Inhibition in HRD+ Tumors

PRMT5 upregulates the expression of DNA repair genes including BRCA 1 , BRCA 2 , RAD5 1 , RAD51D and Ku80 .

Inhibition of PRMT5 reduces expression of these genes and prevents DNA repair, inducing a state of “ BRC A ness” 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.

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

for compounds with low efflux potential followed by confirmatory brain exposure studies in viv o .

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.

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.

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

Preclinical Results—Summary

In vitr o , 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 viv o , 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.

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 vitr o .

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 vitr o , 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.

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 =

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 BRCA 1 , BRCA 2 , ATM and AT R , and was synergistic in combination with PARP inhibitors.

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 viv o , 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 viv o .

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.

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 vitr o , 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.

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).

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).

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

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.

T he 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

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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.

Enrollment into the additional dose expansion cohorts began early in the second quarter of 2021.

Total expected enrollment is anticipated to be approximately 165 patients.

The schema is shown below in 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

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.

Preliminary Day 1 Pharmacokinetics in Solid Tumor Cohort

Doses and Schedules

AUC0-t (nM h)

Day 1 exposure from 35 mg, q.d.

and 35mg, 5x dose levels combined.

5x means once a day, for five days, with two days off.

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 .

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.

Baseline and 8 Week Tumor Assessment CT Scans

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.

Preliminary Day 1 Pharmacokinetics in Myeloid Malignancies Cohort

Doses and Schedules

AUC0-t (nM h)

Exposures from 40 mg, b.i.w.

dose levels combined.

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.

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.

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.

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.

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.

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.

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).

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.

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

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

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.

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).

Student’s t test, 2 tailed.

N=8/arm mg/kg, milligrams/kilogram;

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.

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.

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.

Phase 1 Clinical Trial of PRT543

All data are reflective of a data cutoff of August 6, 2021 unless otherwise stated.

As of an August 6, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT543 enrolled a total of 49 patients across 18 unselected advanced solid tumors and lymphoma.

Patients enrolled received an average of three prior lines of therapy.

PRT543 demonstrated target engagement and inhibition of PRMT5 functional activity as evidenced by a 69% reduction in serum symmetric dimethylarginine, or sDMA, at a dose of 45 mg/5x per week.

In addition, PRT543 demonstrated signs of preliminary clinical activity, including a durable CR, maintained for over 18 months in a patient with HRD+ ovarian cancer who remains on treatment and prolonged SD, persisting for over six months in five patients, including four patients with ACC and one patient with uveal melanoma.

A complete response is defined as the disappearance of all target lesions.

PRT543 was generally well tolerated:

the most common grade 3 or higher treatment-related adverse events, or AE, occurring in at least 5% of patients were thrombocytopenia (27%) and anemia (12%), both of which were reversible upon

treatment interruption.

Patients were largely able to remain on therapy with few AE-related dose interruptions (27%), reductions (22%), or discontinuations (4%).

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.

Based on data from the ongoing Phase 1 dose expansion studies of both PRT543 and PRT811, we announced, on March 9, 2022, that we are concentrating our development efforts on PRT811 in biomarker-selected patients in specific cancer types.

While the Company believes that both PRT811 and PRT543 are high quality, clinically active compounds, PRT811 was selected based on its superior safety profile, higher level of target engagement, and unique brain penetrant properties.

Specifically, we intend to:

Complete data analysis of the ongoing expansion cohort of adenoid cystic carcinoma (ACC) by mid-year to determine further development.

Report data from the ongoing dose expansion cohorts in the second half of 2022.

Our second PRMT5 inhibitor, PRT811 has completed a Phase 1 dose escalation study and is currently enrolling dose expansion cohorts.

Data from the expansion cohorts are expected to be presented in the second half of 2022.

Clinical Trial Design and Schema

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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.

Enrollment initiated in November 2019 and is being conducted across eleven sites in the United States.

We initiated enrollment of the dose expansion portion of the clinical trial in three patient cohorts in December 2021.

The total expected enrollment is approximately 63 patients.

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.

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.

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.

Preliminary Day 1 PRT811 Pharmacokinetics

AUC0-t (nM h)

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.

PRT543 and PRT811 Clinical Trial Schema

Phase 1 Clinical Trial of PRT811

All data are reflective of a data cutoff of August 13, 2021 unless otherwise stated.

The dose escalation portion of the ongoing Phase 1 trial of PRT811 enrolled a total of 45 patients, including 27 patients across 16 unselected advanced solid tumors and 18 patients with high-grade gliomas, including 17 patients with glioblastoma multiforme, or GBM.

PRT811 demonstrated dose dependent inhibition of PRMT5 activity as evidenced by an 83% reduction in serum sDMA at a dose of 600 mg daily (QD).

In addition, PRT811 demonstrated signs of preliminary clinical activity, including an IDH1 mutated high-grade glioma (glioblastoma (GBM)) patient who experienced a PR that evolved into a durable CR for more than 13 months.

In addition, a patient with splicing-mutant, or SF3B1, uveal melanoma demonstrated SD for more than six months with a 25% tumor regression.

PRT811 was generally well-tolerated;

the most common grade 3 or higher treatment-related AE was thrombocytopenia (7%), which was reversible upon treatment interruption.

Patients were largely able to remain on therapy with few AE-related dose interruptions (13%), reductions (4%), or discontinuations (3%).

Based on data from the ongoing Phase 1 dose expansion studies of both PRT543 and PRT811, we announced on March 9, 2022, that we are concentrating our development efforts on PRT811 in biomarker-selected patients in specific cancer types.

Specifically, we intend to:

Report data from the ongoing dose expansion cohorts in the second half of 2022.

Determine appropriate development options for PRT811 based on emerging data from ongoing expansion cohorts.

MCL1 Inhibitor:

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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

published third-party data, we believe that hematological malignancies are particularly sensitive to MCL1 inhibitors.

Based on our preclinical data, as well as 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 th is 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 .

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.

The dose escalation portion of the Phase 1 trial of both oral formulation and the IV formulation, which leverages the optimized physicochemical properties of PRT1419, are now underway in patients with solid tumors.

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.

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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

multiple myeloma clinical trial with AMG176, a third-party MCL1 inhibitor, providing clinical validation of the pathway.

Objective clinical responses were demonstrated in a Phase 1 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.

Although the data on the importance of MCL1 in driving tumor growth and survival are compelling, complete ablation of M CL 1 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.

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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.

In Vitro Potency and Selectivity

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.

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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.

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).

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

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.

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.

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.

Other approved therapies for AML include MYLOTARG (gemtuzumab ozogamicin), an antibody-drug conjugate, as well as a number of targeted therapies for subsets of patients whose tumors harbor specific alterations.

These include RYDAPT (midostaurin) and XOSPATA (gilteritinib) for FLT3-mutated AML, IDHIFA (enasidenib) for IDH2-mutated AML, and TIBSOVO (ivosidenib) for IDH-1 mutated AML.

Despite these recent advances, we believe there remains a need for a well-tolerated and effective therapy that can broadly address AML patients, especially those progressing on front-line therapies and/or venetoclax.

In the registrational

study for venetoclax in combination with azacitidine or decitabine, a composite complete remission, or CRc, of 67% was observed, with a response duration of 11.3 months and a median overall survival, or OS, of 17.5 months.

Non-Hodgkin Lymphoma (NHL)

NHL is a group of blood cancers originating in either B-cells (approximately 85% of all NHL) or T-cells (approximately 15% of all NHL).

The American Cancer Society estimates the incidence of NHL to be over 77,000 patients annually in the United States.

NHL is characterized into subtypes according to the natural course of disease progression.

Aggressive lymphomas, which account for 60% of all NHL cases, progress rapidly.

Diffuse large B-cell lymphoma, or DLBCL, is the most common of these aggressive subtypes.

Indolent lymphomas, which account for 40% of all NHL cases, progress more slowly with fewer symptoms upon diagnosis.

Follicular lymphoma, or FL, is the most common of these indolent subtypes.

The treatment of NHL varies by subtype and can include one of more of the following modalities:

chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, targeted therapy, and cell therapy, or CAR-T.

Despite recent therapeutic advances and approvals, there remains a high unmet need for new NHL treatments, particularly for more aggressive subtypes and for patients who have progressed on standard therapies.

For example, approximately 50% of patients with DLBCL will be refractory to or relapse on standard therapy.

The prognosis for patients with DLBCL who relapse is poor, with median survival of less than one year.

Multiple Myeloma (MM)

MM is a blood cancer originating in the bone marrow that is characterized by excess proliferation of aberrant antibody-producing plasma cells.

MM is the third most common blood cancer, and the American Cancer Society estimates an incidence of over 32,000 patients annually in the United States.

MM is primarily a disease of the elderly and has a five-year survival rate of 54%.

The treatment of MM depends on the aggressiveness of disease and patient fitness.

For patients in good health and with active disease, first-line treatment typically involves high-dose chemotherapy followed by stem cell transplantation if possible.

For patients who do not achieve a CR or who are not candidates for stem cell transplantation, systemic chemotherapy is indicated.

The past two decades have seen significant advances in systemic treatment for MM, including the introduction of immunomodulatory agents, such as REVLIMID (lenalidomide);

monoclonal antibodies, such as DARZALEX (daratumumab);

and proteasome inhibitors, including VELCADE (bortezomib) and KYPROLIS (carfilzomib).

MM therapies generated approximately $19.4 billion in world-wide sales in 2019.

Despite these therapeutic advances, MM remains incurable.

Patients typically receive multiple lines of therapy but ultimately progress.

The median OS for patients who are refractory to both an immunomodulatory drug and proteasome inhibitor is only 13 months.

The in vitro activity of PRT1419 was confirmed in vivo.

Once weekly dosing of PRT1419 demonstrated robust efficacy in preclinical models of AML, DLBCL and multiple myeloma.

Clinical Trial Update

Two dose escalation Phase I studies for our oral and IV formulation of PRT1419 are on-going in patients with hematologic malignancies, including patients with high risk myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM.

A third dose escalation Phase I study for our IV formulation of PRT1419 is on-going for patients with unselected solid tumors.

On March 9, 2022, we announced that based on the data to date, we intend to prioritize development of the IV formulation of PRT1419, which demonstrated a desirable pharmacokinetic, pharmacodynamic and safety profile with potential for differentiation from competitor compounds.

We intend to initiate a combination trial with venetoclax by mid-year with the goal of establishing safety, clinical activity and a recommended Phase 2 dose in the second half of 2022.

CDK9 has emerged as an essential regulator of cancer-promoting transcriptional programs, including those driven by MCL1, MYC and MYB .

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We have applied our internal expertise to design PRT2527 as a potent inhibitor of CDK9 that exhibits high kinome selectivity, PK properties and solubility that we believe may broaden the therapeutic window of CDK9 inhibition.

PRT2527 has entered IND-enabling studies, with IND submission expected in 2021.

A phase 1 trial is underway evaluating escalating IV doses of PRT2527 as a monotherapy in patients with selected solid tumors, including sarcoma, prostate cancer, lung cancer, and other cancers with genomic alterations that lead to MYC dependence.

Cyclin dependent kinases, or CDKs, are a family of closely related serine/threonine kinases that have demonstrated activity in multiple cancers.

The first inhibitors of two of the family members, CDK4 and CDK6, gained FDA approval for HR+ metastatic breast cancer in 2015 and are now broadly used.

In contrast to CDK4 and CDK6, which regulate cell cycle progression and proliferation, it is now appreciated that other members of the CDK family play important roles in

regulating transcription.

In contrast to CDK4 and CDK6, which regulate cell cycle progression and proliferation, it is now appreciated that other members of the CDK family play important roles in regulating transcription.

CDK9 specifically phosphorylates RNA polymerase II to generate mature mRNA.

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In preclinical models, PRT2527 reduced MCL1 and MYC protein levels and was highly active in the MYC - amplified MV4-11 xenograft model at well-tolerated doses.

Upon evaluation of additional models, PRT2527 treatment demonstrated robust efficacy in both hematological malignancies and solid tumor models with MYC dysregulation.

Our preclinical studies suggest that PRT2527 demonstrates high selectivity and high potency, providing opportunity for a wider therapeutic index compared to less selective CDK9 inhibitors.

SMARCA2 targeted degrader program

We intend to complete enrollment in the Phase 1 dose escalation study of PRT2527 with the goal of identifying a recommended Phase 2 dose in the second half of 2022.

CDK4/6 Program

Among the CDK subfamily of kinases, CDK4 and CDK6 are the master regulators that control entry of cells into cell cycle.

Given the central roles that CDK4 and CDK6 play in cell cycle regulation, dysregulation of the CDK4/CDK6 pathway has been frequently observed in cancer and CDK4/CDK6 have been intensively investigated as potential therapeutic targets for cancer treatment.

The approval of three CDK4/CDK6 selective inhibitors in combination with endocrine therapies, to treat hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer has further validated this hypothesis.

Despite the success of CDK4/CDK6 inhibitors for the treatment of ER+ metastatic breast cancer, central nervous system (CNS) diseases such as glioblastoma (GBM) and brain metastases are challenging malignancies with urgent unmet needs.

Large scale genomic studies revealed that the CDK4/CDK6 pathway is disrupted in the majority of gliomas, suggesting CDK4/CDK6 may be good targets for GBM.

In addition, brain metastases may arise in an estimated 20% of all cancer patients but still lacks effective therapies.

Genomic studies also identified the CDK4/6 pathway as one of three most altered and actionable genetic alternations in brain metastasis.

However, despite positive preclinical data supporting targeting CDK4/CDK6 to treat CNS cancers, clinical development of CDK4/CDK6 inhibitors for GBM or brain metastases has not been successful, likely due to the inability of current inhibitors to penetrate the blood-brain barrier (BBB) and achieve effective concentrations in the brain.

Our CDK4/6 Inhibitor:

Structure based design and iterative compound synthesis and testing led to the identification of PRT3645, a highly brain penetrant molecule that potently and selectively targets CDK4/6.

In cellular assays, PRT3645 inhibits phosphorylation of RB, a substrate of CDK4/CDK6, with low nanomolar activity.

Consistent with this, PRT3645 treatment results in concentration-dependent inhibition of cell proliferation in glioblastoma (GBM) cell lines and in ER+/HER2- and HER2+ breast cancer lines.

In vivo, orally administered PRT3645 was well tolerated and highly efficacious in a dose-dependent manner in orthotopic human breast cancer brain metastasis and GBM models.

In a head to head comparison, PRT3645 demonstrated a brain:plasma ratio that was ~100x higher than approved CDK4/6 inhibitors.

We plan to complete IND-enabling studies, file an IND and initiate a Phase 1 clinical trial in the second half of 2022.

SMARCA2 (BRM) targeted degrader program

SMARCA2 (also known as BRM) and its related family member, SMARCA4 (also known as BRG1), are the enzymatic subunits of the SWI/SNF complex that regulates gene expression by allowing the DNA to be accessible for transcription to mature RNA, a process known as chromatin remodeling.

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DC50 is a quantitative measure of how much of a compound is needed to inhibit the degradation of a protein by 50%.

We have designed our

SMARCA2 degraders to be potent and selective to specifically inhibit SMARCA4- deficient human NSCLC cell lines and primary patient derived samples.

Optimization of the PK and physical properties suitable for oral, IV or SC dosing is on-going with the goal of initiating IND-enabling studies in 2021.

Kinase Program in Solid Tumors

We are evaluating a kinase that has been shown in preclinical studies to be an oncogenic driver in cancer.

Genomic alterations in this kinase have been identified in multiple tumor types and these tumors are sensitive inhibitors of this kinase in preclinical models.

Current inhibitors of this kinase in development lack optimal PK and biodistribution properties.

Our goal is to identify novel, potent, selective, oral inhibitors of this kinase that have an optimized PK profile for clinical development in patients with solid tumors.

Optimization of our lead kinase inhibitor, PRT-K4, is ongoing with the goal of initiating IND-enabling studies in 2021.

We have designed our SMARCA2 degraders to be potent and selective to specifically inhibit SMARCA4- deficient human NSCLC cell lines and primary patient derived samples.

We are currently profiling our lead compound, PRT-SCA2, and plan to submit an IND application by year-end 2022.

Intellectual Property

We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the compositions of matter of our product candidates, their methods of use, related technology, and other inventions that are important to our business.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions, and know-how related to our business, to defend and enforce our patents, to preserve the confidentiality of our trade secrets, and to operate without infringing valid and enforceable patents and other proprietary rights of third parties.

proprietary rights of third parties.

We also rely on know-how and continuing technological innovation to develop, strengthen, and maintain our proprietary position in the field of precision oncology.

As more fully described below, our patent portfolio includes patent families with claims directed to compositions of matter for, and methods of using, compounds PRT543, PRT811 PRT1419, PRT2527, and compounds that degrade SMARCA2.

patent directed to PRT543 has issued and is expected to expire no earlier than August 9, 2038.

In addition, a U.S.

patent directed to PRT811 has issued and is expected to expire no earlier than March 14, 2039.

In addition to our filings in the United States, we own patent applications that are pending in Australia, Brazil, Canada, China, Eurasia, Europe, Israel, Hong Kong, India, Japan, Korea, Mexico, New Zealand, Ukraine, and South Africa.

Included in these applications are claims directed to the PRT543 composition and methods of using the same therapeutically.

The patents from these applications, if issued, are expected to expire in August

2038, subject to any disclaimers or extensions.

As more fully described below, our patent portfolio includes, inter alia, patent families with claims directed to compositions of matter for, and methods of using, compounds PRT543, PRT811 PRT1419, PRT2527, PRT3645, and compounds that degrade SMARCA2.

The patent portfolio currently comprises of 146 patents and patent applications:

(i) 8 issued U.S.

patents, (ii) 16 U.S.

non-provisional patent applications, and (iii) 23 U.S.

provisional patent applications;

(iv) 13 PCT patent applications, (v) 20 issued foreign patents including patents in the European jurisdictions, and (vi) 66 foreign patent applications.

As of the present filing, a total of eight U.S.

patents have been issued, which are wholly owned by us.

Specifically, a total of three U.S.

patent directed to PRT543 have issued and are expected to expire no earlier than August 9, 2038.

Similarly, three U.S.

patents directed to PRT811 have issued and are expected to expire no earlier than March 14, 2039.

Also, one U.S.

patent directed to the PRMT5 program has issued and is expected expire no earlier than August 16, 2039.

In addition, one U.S.

patent directed to PRT1419 has issued and is expected to expire no earlier than November 08, 2039.

In addition to our filings in the United States, we own patent applications that are pending in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.

Included in these applications are claims directed to the PRT543, PRT811, and PRT1419 composition and methods of using the same therapeutically.

For the PRT543 compound, the patents from these applications, if issued, are expected to expire in August 2038, subject to any disclaimers or extensions.

For the PRT811 compound, the patents from these applications, if issued, are expected to expire in March 2039, subject to any disclaimers or extensions.

For the PRT1419 compound, the patents from these applications, if issued, are expected to expire in November 2039, subject to any disclaimers or extensions.

The patent portfolios for our most advanced programs are summarized below.

Our PRT543 patent portfolio is wholly owned by us.

The portfolio includes one issued U.S.

patent, which claims, among other things, PRT543, pharmaceutical compositions comprising PRT543, methods of inhibiting PRMT5 using PRT543, and methods of treating certain cancers, including breast and ovarian cancers, using PRT543.

patent is expected to expire no earlier than August 9, 2038, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

Corresponding patent applications are pending in several other countries and regions, including Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Israel, India, Japan, Korea, Mexico, New Zealand, Ukraine, and South Africa.

The portfolio includes three issued U.S.

patents, which claim, among other things, PRT543, pharmaceutical compositions comprising PRT543, methods of inhibiting PRMT5 using PRT543, and methods of treating certain cancers, including breast and ovarian cancers, using PRT543.

patents are expected to expire no earlier than August 9, 2038, subject to any disclaimers or extensions available, including under the Hatch-Waxman Act.

Corresponding patent applications are pending in several other countries and regions, including Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.

Any patents resulting from these patent applications, if issued, are also expected to expire no earlier than August 9, 2038, subject to any disclaimers or extensions.

The PRT543 patent portfolio also includes three pending U.S.

and two pending PCT patent applications, which claim, among other things, a genus of compounds that encompass PRT543, PRT543 salts and crystalline forms, methods of preparing PRT543, and additional methods of treatment using PRT543.

patents issuing from these applications would be expected to expire no earlier than August 9, 2038, February 13,

2040, April 3, 2040, and December 10, 2041 respectively, subject to any disclaimers or extensions.

The PRT543 patent portfolio also includes four pending U.S.

and one pending PCT patent applications, which claim, among other things, a genus of compounds that encompass PRT543, PRT543 salts and crystalline forms, methods of preparing PRT543, and additional methods of treatment using PRT543.

patents issuing from these applications would be expected to expire no earlier than August 9, 2038, August 13, 2041;

October 5, 2041;

9 and December 9, 2041, respectively, subject to any disclaimers or extensions.

The PRT543 patent portfolio also includes six pending U.S.

provisional applications that relate to among other things, methods of inhibiting PRMT5 using PRT543, methods of treating certain cancers, and associated clinical studies.

Any patents granted that claim priority to this provisional application could expire as late as 2042.

Our PRT811 patent portfolio is wholly owned by us.

The portfolio includes one issued U.S.

patent, which claims, among other things, PRT811, pharmaceutical compositions comprising PRT811, methods of inhibiting PRMT5 using PRT811, and methods of treating certain cancers, including glioblastoma, using PRT811.

The patent is expected to expire no earlier than March 14, 2039, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

A related PCT application was filed, and corresponding national phase applications were filed in Australia, Brazil, Canada, China, Eurasia, Europe, India, Israel, Japan, Korea, Mexico, New Zealand, Ukraine and South Africa.

The portfolio includes three issued U.S.

patents, which claim, among other things, PRT811, pharmaceutical compositions comprising PRT811, methods of inhibiting PRMT5 using PRT811, and methods of treating certain cancers, including glioblastoma, using PRT811.

The patents are expected to expire no earlier than March 14, 2039, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

PCT application was filed, and corresponding national phase applications were filed in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.

Any patents resulting from these national patent applications, if issued, are expected to expire no earlier than March 14, 2039, subject to any disclaimers or extensions.

The PRT811 patent portfolio also includes two pending U.S.

non-provisional applications, a first PCT application that claims compositions of matter, and a second PCT application that claims methods of treatment.

Any patents issuing from the two pending U.S.

non-provisional applications would be expected to expire in 2039, and any patents issuing from the two PCT applications would be expected to expire in 2040, subject to any disclaimers or extensions.

Our PRT1419 patent portfolio, which is wholly owned by us, includes pending U.S.

patent applications claiming, among other things, PRT1419 and other compounds, pharmaceutical compositions comprising PRT1419, and methods of using PRT1419.

Any patents issued from this application would be expected to expire no earlier than November 8, 2039, subject to any disclaimers or extensions.

A related PCT application was filed and national patent applications based on that application are planned for filing in non-U.S.

countries in May and June 2021.

Any patents resulting from these national patent applications, if issued, would expire no earlier than November 8, 2039, subject to any disclaimers or extensions.

The PRT1419 patent portfolio also includes a pending U.S.

provisional application that claims additional compositions of matter.

non-provisional applications and two PCT applications that claim compositions of matter, and s methods of treatment.

Any patents issuing from the one pending U.S.

non-provisional application would be expected to expire no earlier than April 03, 2020, and any patents issuing from the two PCT applications would be expected to expire not earlier than 2039 and 2040respectively, subject to any disclaimers or extensions.

The PRT811 patent portfolio also includes three pending U.S.

provisional applications that relate to among other things, methods of inhibiting PRMT5 using PRT811, and methods of treating certain cancers, and associated clinical studies.

Any patents granted that claim priority to this provisional application could expire as late as 2042.

Our PRT1419 patent portfolio, which is wholly owned by us.

The portfolio includes one issued U.S.

patent, which claims among other things, PRT1419 and other compounds, pharmaceutical compositions comprising PRT1419, and methods of using such compounds.

The patent is expected to expire no earlier than November 8, 2039, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

A related PCT application was filed, and corresponding national phase applications were filed in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.

Any patents resulting from these national patent applications, if issued, are expected to expire no earlier than November 08, 2039, subject to any disclaimers or extensions.

The portfolio also included one pending U.S.

non-provisional patent application, which claims among other things, PRT1419 related compounds, pharmaceutical compositions comprising PRT1419 related compounds, and methods of using such compounds.

Any patents issued from this application would be expected to expire no earlier than August 17, 2041, subject to any disclaimers or extensions.

Our PRT2527 patent portfolio, which is wholly owned by us, includes one U.S.

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non-provisional and PCT applications would be expected to expire no earlier than 2040, subject to any disclaimers or extensions.

The PRT2527 patent portfolio also includes two pending U.S.

provisional applications that relate to among other things, methods of inhibiting CDK9 using PRT2527 related compounds and methods of treating certain cancers.

Any patents granted that claim priority to this provisional application could expire as late as 2041.

Our PRT3645 patent portfolio, which is wholly owned by us, includes two pending U.S.

non-provisional patent applications and two corresponding PCT applications claiming, among other things, genera of compounds that encompass PRT3645 and other compounds, and/or related inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors.

Any patents issued from the U.S.

patent applications would be expected to expire no earlier than September 21, 2041, and December 17, 2041, respectively, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

The PRT3645 patent portfolio also includes two pending U.S.

provisional applications that, among other things, encompass PRT3645 and/or related CDK inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors.

Any patents granted that claim priority to this provisional application could expire as late as 2042.

SMARCA2 Degraders

The SMARCA2 degrader patent portfolio includes one pending non-provisional U.S.

application, one PCT application, and two U.S.

provisional applications which claim, among other things, genera of compounds that encompass SMARCA2 and/or related inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors.

In addition, we have patent portfolios that are directed to a number of different compounds other than PRT543, PRT811, PRT1419, PRT2527, and SMARCA2 degraders.

The SMARCA2 degrader patent portfolio includes two pending non-provisional U.S.

applications and two corresponding PCT applications, which claim, among other things, genera of compounds that encompass SMARCA2 and/or related inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors.

Any patents issued from the U.S.

patent applications would be expected to expire no earlier than June 09, 2041 and November 08, 2041, respectively, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

The SMARCA2 patent portfolio also includes one pending U.S.

provisional application that, among other things, encompass SMARCA2 and/or related inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors.

Any patents granted that claim priority to this provisional application could expire as late as 2042.

In addition, we have patent portfolios that are directed to a number of different compounds other than PRT543, PRT811, PRT1419, PRT2527, PRT3645, SMARCA2 degraders, and CDK inhibitors.

We have patent applications directed to compounds that target resistance mechanisms in cancer.

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provisional patent applications, U.S.

non-provisional patent applications, foreign applications, and PCT applications, covering compositions and methods of making and using those compounds to treat cancer and other diseases.

non-provisional patent applications, and PCT applications, covering compositions and methods of making and using those compounds to treat cancer and other diseases.

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

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We rely on third parties for storage and distribution of drug substance and drug product.

We do not currently have arrangements in place for redundant supply for active pharmaceutical ingredients and drug product.

We do not currently have arrangements in place

for redundant supply for active pharmaceutical ingredients and drug product.

As our development programs progress and we build new process efficiencies, we expect to continually evaluate this strategy with the objective of satisfying demand for registration trials and, if approved, the manufacture, sale and distribution of commercial products.

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We face competition from segments of the pharmaceutical, biotechnology and other related markets that pursue the development of precision oncology therapies optimized to target the key driver mechanisms in cancers with high unmet need.

Several biopharmaceutical companies, including Black Diamond Therapeutics, Inc., Constellation Pharmaceuticals, Inc., Kronos Bio, Inc., Repare Therapeutics Inc., Revolution Medicines, Inc., Relay Therapeutics, Inc., Vincerx Pharma, Inc.

and Zentalis Pharmaceuticals, Inc., are developing precision oncology medicines.

In addition, we may face competition from companies developing product candidates that are based on targeting pathways of adaptive resistance, including Amgen, AbbVie, AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Pfizer, Bayer and Novartis.

Several biopharmaceutical companies, including Arvinas Inc., Aurigene, Black Diamond Therapeutics, Inc., Boehringer Ingelheim, C4 Therapeutics, Constellation Pharmaceuticals, Inc., Eli Lilly and Company, F.

Hoffman-La Roche, Foghorn Therapeutics Inc., Fochon Pharmaceuticals, G1 Therapeutics Inc., Genentech, Kronos Bio, Inc., Kura Oncology, Inc., Kymera Therapeutics Inc., Mirati Therapeutics Inc., Nuvation Bio Inc.

Repare Therapeutics Inc., Revolution Medicines, Inc., Relay Therapeutics, Inc., Springworks Therapeutics, Inc., Syndax Pharmaceuticals, Inc., and Zentalis Pharmaceuticals, Inc., are developing precision oncology medicines.

In addition, we may face competition from companies developing product candidates that are based on targeting pathways of adaptive resistance, including Amgen Inc., AbbVie Inc., AstraZeneca plc, GlaxoSmithKline plc, Ideaya Biosciences, Johnson & Johnson Services, Inc., Pfizer Inc., Tango Therapeutics, Inc., Vincerx Pharma, Inc., Novartis AG, and Gilead Sciences, Inc.

Furthermore, we also face competition more broadly across the oncology market for cost-effective and reimbursable cancer treatments.

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In addition, many companies are developing new oncology therapeutics, and we cannot predict what the standard of care will be as our product candidates progress through clinical development.

With respect to our PRMT5 programs, PRT543 and PRT811, several companies are developing PRMT5 inhibitors with clinical trials ongoing, including GlaxoSmithKline (GSK3326595), Johnson & Johnson (JNJ-64619178) and Pfizer (PF-06939999).

For our product candidate PRT1419, other companies are developing MCL1 inhibitors with monotherapy and/or combination trials ongoing, including Amgen (AMG176), AstraZeneca (AZD5991) and Novartis (MIK665).

For our preclinical CDK9 program, both AstraZeneca and Bayer have CDK9 programs in Phase 1 clinical trials.

With respect to our PRMT5 programs, PRT543 and PRT811, several companies are developing PRMT5 inhibitors with clinical trials ongoing, including Amgen (AMG193), GlaxoSmithKline (GSK3326595), Ideaya Biosciences (IDE397),

Johnson & Johnson (JNJ-64619178), Pfizer (PF-06939999), and Tango Therapeutics (TNG908).

For our CDK9 program, PRT2527, AstraZeneca (AZD4573), Vincerx (VIP512), and Kronos (KB-0742) have CDK9 programs in Phase 1 clinical trials.

For our CDK4/6 inhibitor program, PRT3645 Novartis ( ribociclib ), Lilly ( abemaciclib ), Pfizer ( palbociclib ), G1 Therapeutics (G1T38), and Fo c hon Pharmaceuticals (FCN-437) have clinical trials ongoing.

For our SMARCA 2 (BRM) degrader program, other companies, including Amgen, Aurigene , C4 Therapeutics , F.

Hoffman-La Roche, Foghorn Therapeutics, Inc., Kymera Therapeutics , Arvinas , Genentech, Boehringer Ingelheim, and Lilly have publicly disclosed their pre-clinical research efforts.

We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient to administer, are less expensive or with more favorable labeling than our product candidates.

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FDA Approval Process

In the United States, pharmaceutical products are subject to extensive regulation by the Food and Drug Administration, or FDA, The Federal Food, Drug, and Cosmetic Act, or FD&C Act, and other federal and state statutes and regulations govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling and import and export of pharmaceutical products.

In the United States, pharmaceutical products are subject to extensive regulation by the FDA, The Federal Food, Drug, and Cosmetic Act, or FD&C Act, and other federal and state statutes and regulations govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling and import and export of pharmaceutical products.

Failure to comply with applicable U.S.

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(i) in compliance with federal regulations;

(ii) in compliance with good clinical practice, or GCP, an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors;

(ii) in compliance with good

clinical practice, or GCP, an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors;

as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

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For example, a Phase 1/2 clinical trial may contain both a dose- escalation stage and a dose-expansion stage, the latter of which may confirm tolerability at the recommended dose for expansion in future clinical trials (as in traditional Phase 1 clinical trials) and provide insight into the anti-tumor effects of the investigational therapy in selected subpopulation(s).

Typically, during the development of oncology therapies, all subjects enrolled in Phase 1 clinical trials are disease-affected patients and, as a result, considerably more information on clinical activity may be collected during such trials than

during Phase 1 clinical trials for non-oncology therapies.

A single pivotal trial may be sufficient in rare instances to provide substantial evidence of effectiveness (generally subject to the requirement of additional post-approval studies).

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Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The applicant under an approved NDA is also subject to annual program fees.

The applicant under an

approved NDA is also subject to annual program fees.

The FDA adjusts the user fees on an annual basis, and the fees typically increase annually.

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An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

As a condition of NDA approval, FDA may require a risk evaluation and

mitigation strategy, or REMS, to help ensure that the benefits of the drug outweigh the potential risks to patients.

As a condition of NDA approval, FDA may require a risk evaluation and mitigation strategy, or REMS, to help ensure that the benefits of the drug outweigh the potential risks to patients.

A REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use, or ETASU.

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Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large studies to demonstrate a clinical or survival benefit.

The accelerated approval pathway is contingent on a sponsor’s agreement to conduct additional post-approval confirmatory studies to verify

and describe the product’s clinical benefit.

The accelerated approval pathway is contingent on a sponsor’s agreement to conduct additional post-approval confirmatory studies to verify and describe the product’s clinical benefit.

These confirmatory trials must be completed with due diligence and, in most cases, the FDA may require that the trial be designed, initiated, and/or fully enrolled prior to approval.

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FDA must determine if the product candidate qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.

The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical studies in an efficient manner.

The FDA may take certain actions with respect to breakthrough therapies, including holding

meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical studies in an efficient manner.

Under the Orphan Drug Act, FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States but for which there is no reasonable expectation that the cost of developing and making the product for this type of disease or condition will be recovered from sales of the product in the United States.

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Drug manufacturers and certain of their subcontractors are required to register their establishments with FDA and certain state agencies.

Registration with FDA subjects entities to periodic unannounced inspections by FDA, during which the Agency inspects manufacturing facilities to assess compliance with cGMPs.

Registration with FDA subjects entities to

periodic unannounced inspections by FDA, during which the Agency inspects manufacturing facilities to assess compliance with cGMPs.

Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality-control to maintain compliance with cGMPs.

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The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice letter.

received, expiration of the patent, the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid or not infringed, or a decision in the patent case that is favorable to the ANDA applicant.

The filing of a patent infringement lawsuit within 45 days of the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months from the date the notice letter is received, expiration of the patent, the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid or not infringed, or a decision in the patent case that is favorable to the ANDA applicant.

The ANDA application also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the referenced product has expired.

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Upon NDA approval of a new chemical entity, or NCE, which is a drug that contains no active moiety that has been approved by FDA in any other NDA, that drug receives five years of marketing exclusivity during which FDA cannot receive any ANDA seeking approval of a generic version of that drug unless the application contains a Paragraph IV certification, in which case the application may be submitted one year prior to expiration of the NCE exclusivity.

If there is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA for a generic version of the drug may be filed before the expiration of the exclusivity period.

is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA for a generic version of the drug may be filed before the expiration of the exclusivity period.

Certain changes to an approved drug, such as the approval of a new indication, the approval of a new strength, and the approval of a new condition of use, are associated with a three-year period of exclusivity from the date of approval during which FDA cannot approve an ANDA for a generic drug that includes the change.

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In particular, for a diagnostic, the applicant must demonstrate that the diagnostic has adequate sensitivity and specificity, has adequate specimen and reagent stability, and produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.

As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.

As part of the PMA review, the FDA will typically inspect the manufacturer’s

facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.

PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

19 unchanged sentences

Pharmaceutical and other healthcare companies have been prosecuted under these laws for, among other things, allegedly inflating drug prices they report to pricing services, which in turn were used by the government to set Medicare and Medicaid reimbursement rates, and for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.

In addition, certain

marketin g practices, includin g off-labe l promotion , ma y als o violat e fals e claim s laws .

Mos t state s als o hav e statute s o r regulations simila r t o th e federa l Anti-Kickbac k Statut e an d civi l Fals e Claim s Act , whic h appl y t o item s an d services reimburse d unde r Medicai d an d othe r stat e programs , or , i n severa l states , appl y regardles s o f th e payor.

In addition, certain marketing practices, including off-label promotion, may also violate false claims laws.

Most states also have statutes or regulations similar to the federal Anti-Kickback Statute and civil False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

Other federal statutes pertaining to healthcare fraud and abuse include the civil monetary penalties statute, which prohibits, among other things, the offer or payment of remuneration to a Medicaid or Medicare beneficiary that the offeror or payor knows or should know is likely to influence the beneficiary to order a receive a reimbursable item or service from a particular supplier, and the additional federal criminal statutes created by the Health Insurance Portability and Accountability Act of 1996, or HIPAA, which prohibits, among other things, knowingly and willfully executing or attempting to execute a scheme to defraud any healthcare benefit program or obtain by means of false or fraudulent pretenses, representations or promises any money or property owned by or under the control of any healthcare benefit program in connection with the delivery of or payment for healthcare benefits, items or services.

18 unchanged sentences

Efforts to ensure that business arrangements with third parties comply with applicable healthcare laws and regulations involve substantial costs.

imprisonment, the curtailment or restructuring of its operations, loss of eligibility to obtain approvals from the FDA, exclusion from participation in government contracting, healthcare reimbursement or other federal or state government healthcare programs, including Medicare and Medicaid, integrity oversight and reporting obligations, imprisonment, and reputational harm.

Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated.

If a drug company’s operations are found to be in violation of any such requirements, it may be subject to significant penalties, including civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, the curtailment or restructuring of its operations, loss of eligibility to obtain approvals from the FDA, exclusion from participation in government contracting, healthcare reimbursement or other federal or state government healthcare programs, including Medicare and Medicaid, integrity oversight and reporting obligations, imprisonment, and reputational harm.

Although effective compliance programs can mitigate the risk of investigation and prosecution for

violations of these laws, these risks cannot be entirely eliminated .

Any action for an alleged or suspected violation can cause a drug company to incur significant legal expenses and divert management’s attention from the operation of the business, even if such action is successfully defended.

15 unchanged sentences

On August 2, 2011, the Budget Control Act of 2011 among other things, created measures for spending reductions by Congress.

A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

A Joint Select Committee on Deficit Reduction,

tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

This includes aggregate reductions of Medicare payments to providers of 2% per fiscal year.

20 unchanged sentences

On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule, and it faces uncertain prospects for implementation.

on certain product access and marketing cost disclosure and transparency measures, and, in most cases, designed to encourage importation from other countries and bulk purchasing.

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

It is possible that additional governmental action is taken to address the COVID-19 pandemic.

48 unchanged sentences

The safety, health and wellness of our employees is a top priority.

In response to COVID-19, we have implemented a safety protocols including shift work scheduling to reduce number of people in the facility, requirements for the wearing of masks and for social distancing, increased cleaning procedures and readily available hand sanitizer.

In response to the COVID-19 pandemic, we have implemented a safety protocols including shift work scheduling to reduce number of people in the facility, requirements for the wearing of masks and for social distancing, increased cleaning procedures and readily available hand sanitizer.

These protocols are designed to comply with health and safety standards as required by federal, state and local government agencies, taking into consideration guidelines of the Centers for Disease Control and Prevention and other public health authorities.

7 unchanged sentences

The mark “Prelude Therapeutics,” the Prelude logo and all product names are our common law trademarks.

All other service marks, trademarks and trade names appearing in this Annual Report on Form 10-K are the property of their

respective owners.

Solely for convenience, the trademarks and tradenames referred to in this Annual Report on Form 10-K appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.

All other service marks, trademarks and trade names appearing in this Annual Report on Form 10-K are the property of their respective owners.

Solely for convenience, the trademarks and tradenames referred to in this Annual Report on Form 10-K appear

without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.

Available Information

We make available free of charge on our website our Annual Report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports as soon as reasonably practicable after we electronically file or furnish such materials to the Securities and Exchange Commission, or SEC.

We make available free of charge electronic versions of our Annual Report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports on our website, preludetx.com, as soon as reasonably practicable after we electronically file or furnish such materials to the Securities and Exchange Commission, or SEC.

The reports are also available at www.sec.gov.

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

What changed 10-K

Item 1. Business