be of limited benefit. To circumvent these challenges, previous drug development efforts have primarily focused on gene therapy delivery of wild type p53 or drugs that disrupt interaction with proteins that control p53 activation and abundance. We believe the more effective approach is our direct conformational reactivation of mutant p53 and restoration of wild‑typewild-type structure and activity, independent of the type of mutation.

Our approach to re-activating p53

One of the most attractive features of apoptosis activation as a cancer therapy is its potential to induce tumor regression rather than to simply stop tumor growth. However, pro‑apoptoticpro-apoptotic agents that cannot discriminate between malignant and normal cells carry a significant risk of side effects. This is an important issue with traditional cancer treatments: radiotherapy and chemotherapy induce apoptosis only as a secondary effect of the cellular damage they induce. These treatments affect most proliferating cells without distinction between malignant or normal cells. Our product candidates, in contrast, are designed to reactivate mutant, non‑functionalnon-functional p53 to restore normal apoptotic functions in cancer cells without triggering apoptosis in normal cells, thereby selectively enhancing the effects of other chemotherapy drugs in malignant cancer cells with mutant p53.

APR‑246Eprenetapopt and the MQ, have been extensively studied. MQ‑modifiedMQ-modified mutant p53 protein has been shown to induce significant levels of apoptosis, indicating that covalent binding of MQ activates mutant p53 and induces a p53‑dependentp53-dependent apoptotic response. Experiments by our founders looking directly at the conformational state of p53 protein in cells have confirmed that binding of MQ stabilizes mutant p53 in the functional, wild type conformation. Structural biology studies performed by our collaborators have produced the first‑everfirst-ever crystal structures of several single‑sitesingle-site missense mutant p53 forms bound to DNA. These structures confirm both the sites of MQ binding to mutant p53 and the stabilization of mutant p53 by MQ in the wild type conformation.conformation (Degtjarik et al, Nat Commun, 2021). Reactivation of mutant p53 via stabilization of the properly folded wild type conformation is the key step in our product candidates’ mechanism of action. The following diagram illustrates this mechanism.

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In in vitro and in vivo experiments, our lead p53 re‑activatingre-activating product candidate, APR‑246,eprenetapopt, via MQ, impaired tumor cells’ capacity to respond to oxidative stress. In parallel to binding mutant p53, and as published by Liu et al, Nat Commun, 2017, 14844, MQ depletes intracellular glutathione, or GSH, and induces reactive oxygen species, or ROS. Furthermore, as published in Peng et al, Cell Death Dis, 2013, e881, MQ has been shown to inhibit the reductase activities of the redox enzyme thioredoxin reductase, or TrxR1, and convert the enzyme to a dedicated oxidase, thereby increasing levels of ROS. Additional results reported in Haffo et al, Sci. Reports, 2018, 12671, have demonstrated MQ inhibition of thioredoxin, or Trx1, and glutaredoxin, or Grx1, which further augment oxidative stress, and ribonucleotide reductase, or RNR, which decreases the cell’s ability to repair damaged DNA. These effects on the cellular redox system, illustrated in the following diagram, may contribute to the anticancer activity of APR‑246eprenetapopt as well as the selectivity for effects on cancer cells versus healthy normal cells. Malignant cells have higher levels of ROS than healthy

Cell fate is a function of the extent and severity of cellular stresses, such as oxidative stress and DNA damage. A network of proteins translates information about cellular stress into biochemical signals and relays this information back to p53, the center of the network. p53 integrates these biochemical signals and becomes activated to initiate cell cycle arrest. When cellular stress and damage are sufficiently high, such as with chemotherapy, p53 initiates apoptosis. MQ restores the ability of a cell to respond to oxidative stress and DNA damage via reactivation of mutant p53 and induces heightened oxidative stress signals to which reactivated p53 can respond. The overlap of these features of the mechanism of action may in turn provide more efficient induction of apoptosis.

Market opportunity for p53 re-activating product candidates

We believe there is a significant market opportunity for therapies targeting mutant p53 because these mutations occur in more than half of all tumors and confer an inferior prognosis relative to patients with wild type p53. Preclinical anti‑tumoranti-tumor activity has been observed with APR‑246eprenetapopt in a wide variety of hematological and solid tumor models and cell lines as reviewed and referenced in Perdrix et al, Cancer 2017, 9, 172. Given the importance of p53 mutations as disease‑driverdisease-driver mutations, the sensitivity of hematopoietic cells to oxidative stress and continued unmet medical need, we are initiallyhave largely focused in our initial clinical development onin hematological malignancies MDS and AML, with TP53 mutations.

Myelodysplastic syndromes—disease background and opportunity

MDS is a collection of bone marrow disorders in which malignant hematopoietic cells prevent production of healthy, mature blood cells. Low blood cell counts, called cytopenias, are a hallmark feature of MDS and are a principal cause of morbidity and mortality from infection and bleeding. MDS can develop de novo or may arise secondary to chemotherapy or radiation treatment for a different, prior malignancy or following an antecedent hematological disorder. Treatment‑relatedTreatment-related MDS is associated with increased complex chromosomal abnormalities and carries a worse prognosis than de novo MDS. As of 2019, there are an estimated 200,000 MDS patients worldwide, with 68,000 of these in the United States and 69,000 MDS patients across the five major markets of the European Union and Japan. Globally, MDS prevalence is expected to increase 2‑3%2-3% annually in mature markets and 3‑4%3-4% annually in emerging markets as populations age. MDS predominantly affects older adults, with approximately 75% of patients aged 60 years or older at diagnosis. Around 30% of patients diagnosed with MDS will progress to AML, with the rate being higher for patients with more advanced disease.

classified as a complex karyotype, which correlates with poor prognosis, low response to intensive chemotherapy, high rate of relapse and inferior survival. Mutations in TP53 occur in approximately 20% of patients with de novo MDS and in more than 30% of patients with therapy‑relatedtherapy-related MDS who develop disease secondary to chemotherapy or radiation treatment for other cancers. Sequencing of a panel of commonly mutated genes, including TP53, is standard practice in the diagnosis of MDS.

Historically, treatment response rates in TP53 mutant MDS patients have been poor regardless of therapy. Treatment with azacitidine is the standard of care for frontline therapy in TP53 mutant MDS, with ORR of 40‑45%, a CR rate of 20% or less and median OS of approximately 7‑8 months. There are no established curative pharmacologic therapies for MDS. Allo‑HCTMDS.Allo-HCT is currently the only recognized therapy believed to increase the likelihood of long termlong-term survival for TP53 mutant MDS patients; however, many patients are not candidates for allo‑HCTallo-HCT due to lack of sufficient clinical response to initial therapy, advanced age, comorbidities or lack of a suitable donor. Unfortunately, even for those TP53 mutant MDS patients who receive allo‑HCT,allo-HCT, the post‑transplantationpost-transplantation prognosis is poor: TP53 mutations are associated with a 4‑fold4-fold increased risk of death and 1‑year1-year relapse-free survival of only 30% following transplantation.

Given the poor prognosis for patients with TP53 mutant MDS there is a significant need for more effective therapies in this population, particularly if such treatments have a favorable safety profile, a mechanism of action that targets mutant p53 directly, and may be used in combination with existing or future treatment options.

Acute myeloid leukemia—disease background and opportunity

AML is the most common form of adult leukemia, with the highest incidence in patients aged 60 years and older. AML is characterized by proliferation of abnormal immature white blood cells which, like MDS, impairs production of normal blood cells. AML can develop de novo or may arise secondary to progression of other hematologic disorders or from chemotherapy or radiation treatment for a different, prior malignancy; secondary AML carries a worse prognosis than de novo AML. As of 2019, there are an estimated 213,000 AML patients worldwide, with 37,000 of these in the United States and 41,000 across the five major European Union markets and Japan. Globally, AML prevalence is expected to increase approximately 1-2% annually in mature markets and 2-3% in emerging markets.

AML patients are segmented into different risk groups according to cytogenetic abnormalities. The presence of three or more coincident structural genetic abnormalities is classified as a complex karyotype, which correlates with adverse prognosis, low response to intensive chemotherapy, high rate of relapse and inferior survival. Mutations in TP53 occur in approximately 20% of patients with newly diagnosed AML, more than 30% of patients with therapy-related AML and approximately 70-80% of patients with complex karyotype. Sequencing of a panel of commonly mutated genes, including TP53, is standard practice in the diagnosis of AML.

Historically, treatment response rates in TP53 mutant AML patients have been poor regardless of therapy. Treatment with azacitidine is the standard of care therapy for frontline therapy in TP53 mutant AML, with 40-50% ORR, 10-20% CR rate and OS of 7-8 months. Treatment of relapsed/refractory AML with venetoclax and azacitidine provides 40-50% ORR and OS of ~7 months. Similar to MDS, allo-HCT is currently the only recognized therapy believed to increase the likelihood of long termlong-term survival for TP53 mutant AML patients; however, many patients are not candidates for allo-HCT due to lack of sufficient clinical response to therapy, advanced age, comorbidities or lack of a suitable donor. Unfortunately, even for those TP53 mutant AML patients who receive allo-HCT, the post-transplantation prognosis is poor: TP53 mutations areassociated with a 4-fold increased risk of death and 1-year relapse-free survival of only 30% following transplantation.

Given the poor prognosis for patients with TP53 mutant AML there is a significant need for more effective therapies in this population, particularly if such treatments have a favorable safety profile, a mechanism of action that targets mutant p53 directly, and may be used in combination with existing or future treatment options.

Chronic lymphocytic leukemia—disease background and opportunity

Chronic lymphocytic leukemia (CLL) is one of the most common types of B-cell non-Hodgkin lymphoma (NHL), characterized by a progressive accumulation of functionally incompetent monoclonal lymphocytes. As of 2017, the

estimated prevalence of CLL was approximately 205,000 in the United States and approximately 180,000 across the five major European Union markets and Japan.Canada.

Bladder cancer—disease background and opportunity

Bladder cancer is a common cancer worldwide and is more common in men than in women. In 2018, the estimated prevalence of bladder cancer was approximately 275,000 in the United States, approximately 370,000 in the five major European Union markets and approximately 120,000 in Japan.

TP53 mutation occurs in approximately 50% of bladder cancer cases. First-line treatment with platinum agents is standard of care; however, few therapeutic options exist for second-line treatment of patients with platinum-refractory bladder cancer. The humanized anti-PD-1 monoclonal antibody, pembrolizumab, is approved by the US FDA for the treatment of locally advanced or metastatic, PD-L1 positive bladder cancer who are not eligible for cisplatin-containing chemotherapy; in patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status; and in patients who have disease progression during or following platinum-containing chemotherapy. In eligible patients, pembrolizumab achieved 21.1% ORR, 9.3% CR, and median OS of 10.3 months.

Non-small cell lung cancer—disease background and opportunity

Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. In 2019, the estimated prevalence of NSCLC was approximately 312,000 in the United States, 194,000 in the five major European Union markets and approximately 312,000 in Japan.

TP53 mutation occurs in up to 80% of NSCLC cases. The humanized anti-PD-1 monoclonal antibody, pembrolizumab, is approved by the US FDA as a single agent in NSCLC for the first-line treatment of PD-L1 positive metastatic disease or in patients who have progressive disease during or following platinum-containing chemotherapy. As first-line treatment of eligible patients with high PD-L1 expression, pembrolizumab achieved 45% ORR, 4% CR, and median OS of 30 months. In patients with previously treated NSCLC, pembrolizumab achieved 19% ORR, 0% CR and median OS of 12.7 months. Treatment options are limited for patients whose disease is R/R to prior anti-PD-1 therapy.

Our lead product candidate, eprenetapopt

Our lead product candidate, APR-246

Our lead product candidate, APR‑246,eprenetapopt, is a small molecule that has demonstrated reactivation of mutant p53 in both clinical trials and preclinical studies. Promising clinical and preclinical data support the application of APR‑246eprenetapopt across a variety of hematologic malignancies and other oncologic indications. Based on its mechanism of action of p53 reactivation and the complementary increase in oxidative stress, as well as its established synergy with anti‑canceranti-cancer agents as evidenced in preclinical studies, APR‑246eprenetapopt treatment may be effective in a broad range of clinical settings.

receiving both APR‑246patients who received eprenetapopt and azacitidine andazacitidine; of these, 3 were reported by an investigator as possibly related to both study drugs. There has been one death resulting from acute cardiac failure in a patient receiving both APR-246eprenetapopt and azacitidine and 1 as possibly related to eprenetapopt only. Fatal adverse events occurred in 10% of patients who received azacitidine alone; of these 2 were reported by an investigator as possibly related to APR-246, and one death resulting from pneumonitis in a patient receiving azacitidine monotherapy and reported by an investigator as possibly related.azacitidine. The target enrollment is 154 patients and we had anticipated completing enrollment in the first quarter of 2020 and top‑line CR data in the second half of 2020. We have observed a recent decrease in both patient screening and patient enrollment as a result of the recent coronavirus (COVID-19) pandemic. Together with our investigators and clinical sites, we are assessing the potential impact of the coronavirus pandemic and the corresponding impact on enrollment and the ability to maintain patients enrolled in this trial and the corresponding impact on the timing of the completion of the trial and subsequent availability of top-line data.

The U.S. Phase 1b/2 MDS/AML Trial

We are supporting an investigator‑initiated Phase 1b/2 single‑arm, open‑label, multi‑center trial in the United States of APR‑246 with azacitidine in HMA‑naïve patients with TP53 mutant myeloid neoplasms including MDS and AML. Enrollment commenced in May 2017 and was completed in March 2019. The Phase 1b part enrolled 12 patients and was conducted as a dose escalation in a modified 3+3 design at dose levels of 50 mg/kg/d, 75 mg/kg/d and 100 mg/kg/d, calculated by lean body mass. The Phase 2 part enrolled 43 patients with all patients receiving a fixed dose of 4500 mg/d APR‑246, a dose that our population pharmacokinetic analysis has identified as approximately equivalent to the highest Phase 1b dose, 100 mg/kg/d by lean body mass. A lead‑in phase, beginning two weeks prior to starting cycle 1 of combination therapy with azacitidine, was conducted only in the Phase 1b part. The purpose of the lead‑in phase was to establish the adverse event profile of APR‑246 in this patient population and to APR‑246‑induced p53 reactivation. The protocol specifies administration of APR‑246 as a 6‑hour intravenous infusion daily for four consecutive days, with administration of 75 mg/m2/d azacitidine by sub‑cutaneous injection or intravenously beginning on Day 4 after completion of APR‑246 infusion and continuing for 6 additional days. The image below shows the design of the U.S. Phase 1b/2 MDS/AML Trial.

Design of the U.S. Phase 1b/2 MDS/AML Trial

Baseline characteristics of patients enrolled in the trial are shown in the following table. Patients with MDS, AML, chronic myelomonocytic leukemia, or CMML, and MDS‑myeloproliferative neoplasm overlap, or MDS‑MPN, were allowed to enroll in the trial. Most patients were higher risk MDS (35/55, 64%most common (≥5%) or AML (11/55, 20%), with complex karyotypes, cytopenias and transfusion dependence.

Baseline characteristics

The median age of all enrolled patients was 66 years, consistent with MDS and AML affecting mostly older patients. Of the MDS patients in the trial, 36/40 were high or very high risk by IPSS‑R. Across all patients, 33% had documented therapy‑related disease and 85% had complex karyotypes. High risk patients with complex karyotypes and TP53 mutation have been reported to have the poorest prognosis of all MDS and AML patients. The median bone marrow blast percentage was 8%. Hematologic parameters were reflective of the frequently severe cytopenias attendant with MDS and AML and were underscored by transfusion dependence at baseline in 69% of patients.

Of the 51 MDS and AML patients treated with the combination of APR‑246 and azacitidine, 41 had at least one serial bone marrow biopsy performed and were evaluable for response in accordance with trial protocol as of November 15, 2019. In addition, 4 patients with CMML or MDS-MPN were evaluable for response at the same data cutoff. In the subset of 41 evaluable MDS and AML patients, responses were reported in 29/33 (88%) MDS patients and 7/8 (88%) AML patients. In MDS patients, the CR rate was 61%, with an additional 27% achieving non‑CR responses. In AML patients, the CR rate was 50%, with an additional 38% achieving non‑CR responses. Twenty-one of 41 (51%) MDS/AML patients discontinued treatment for allo‑HCT, as transplant is viewed as a potentially curative option for patients with TP53 mutant MDS and AML. Treatment duration and responses are shown in the figure below. The median time to first response was 1.9 months in MDS patients and 2.2 months in AML patients. With a median follow up of 10.8 months, the median duration of response in evaluable patients was 8.0 months (95% confidence interval: 6.5 – 11.2 months) and the median duration of CR was 7.3 months (95% confidence interval: 5.8 months – not estimable). The median duration of response in MDS patients was 8.4 months (95% confidence interval: 6.5 – 13.2 months) and the median duration of CR was 7.3 months (95% confidence interval: 7.3 months – not estimable) in MDS patients and 7.0 months (95% confidence interval: 3.3 months – not estimable) in AML patients. By intention to treat analysis, median OS was 10.8 months (95% confidence interval: 8.1 − 13.4 months) with significantly prolonged OS of 13.7 months (95% confidence interval: 10.8 – 16.5 months) in responding patients versus 3.9 months (95% confidence interval: 1.9 – 6.0 months) in non‑responding patients (p < 0.0001).

Treatment duration and response in evaluable patients in the U.S. Trial

Data cutoff: November 15, 2019 (n=45)

Treatment with azacitidine is the standard of care for frontline therapy in TP53 mutant MDS and AML, with ORR of 40‑45% and a CR rate of 15-20%. A limited number of peer‑reviewed publications have reported the duration of response, or DoR, in this patient population; from the available public data, DoR is approximately 4‑5 months.

Reported adverse events, or AEs, were mostly low‑grade (Grade 1 or 2). Grade 3 or higher AEs were mostly associated with the underlying disease. In the APR‑246 monotherapy lead‑in phase there were no dose‑limiting toxicities, no serious adverse events attributed to APR‑246 and all treatment‑related AEsin patients who received eprenetapopt with azacitidine were low‑grade. The following chart summarizes the AEs reported in more than one patient during the APR‑246 monotherapy lead‑in phase.

AEs reported in > 1 patient during APR-246 monotherapy lead-in phase (n=12)

The most common AEs observed across all cycles of treatment in the trial, as of March  18, 2020 and regardless of causality, are summarized in the following chart. Only three patients (5%) discontinued treatment due to AE. Serious adverse events, regardless of causality, reported for more than one patient were: febrile neutropenia (33%), pneumonia (20%(11%), sepsis (11%), lung infection (9%), pyrexia (7%(8%), dehydration (5%), musclemuscular weakness (5%(7%), and respiratory failure (5%), vomiting (5%), angina (4%), atrial fibrillation (4%), embolism (4%), intracranial hemorrhage (4%), multi-organ failure (4%).

Most common reported AEs with APR-246 + azacitidine treatment, regardless of causality (≥20%)

Data cutoff: November 15, 2019 (n=55)

The most common AEs, determined by an investigator to be possibly, probably or definitely related to APR-246 or azacitidine, are summarized in the following chart.

Most common reported AEs with possible, probable or definite relation to APR-246 or azacitidine (≥10%) Data cutoff: November 15, 2019 (n=55)

Sixty-six TP53 mutations, representing 49 unique mutations, were identified in the subset of 45 evaluable patients. Consistent with prior published findings, the majority of these were missense mutations (80%) and located in the DNA‑binding domain (94%). Other TP53 mutations sequenced in the 45 evaluable patients included insertion‑deletion mutations (3%), splice‑site mutations (6%), frameshift mutations (5%) and nonsense mutations (6%). Patients with a TP53 mutation alone predicted for CR (69% vs 25%, P=0.0062) with a trend for higher ORR (93% vs 69%, P=0.08). The distribution of TP53 mutations by type and breadth of mutations by response are shown in the figure below.

TP53 mutations by type and best response in evaluable patients

Data cutoff: November 15, 2019 (n=45)

The French Phase 1b/2 MDS/AML Trial

We are supporting an ongoing investigator‑initiated single‑arm, open‑label Phase 1b/2 trial in France by the Groupe Francophone des Myélodysplasies, or GFM, under lead investigator Prof. Pierre Fenaux, to expand the adverse event and efficacy data set in MDS and AML patients treated with the combination of APR‑246 and azacitidine. The trial was initiated in September 2018 and reached final enrollment of 53 patients in July 2019. The median age of enrolled patients is 73 years. 34 of 53 patients (64%) had a diagnosis of MDS and 19 of 53 patients (36%) had a diagnosis of AML. At baseline, 82% of MDS patients were very high risk by IPSS‑R. Complex karyotype was found in 87% of enrolled patients.

The protocol specifies daily administration of 4500 mg/d APR‑246 as a 6‑hour intravenous infusion daily for four consecutive days, with administration of 75 mg/m2/d azacitidine by sub‑cutaneous injection or intravenously beginning on Day 4 after completion of APR‑246 infusion and continuing for 6 additional days. Treatment cycles are 28 days in duration.   Patients who receive benefit from frontline therapy and undergo allo‑HCT are eligible to continue with

post‑transplant maintenance therapy with APR‑246 and azacitidine. Data were reported in December 2019 for 38 patients evaluable for response in accordance with trial protocol, including 27 MDS patients and 11 AML patients. Responses were achieved in 20/27 (74%) MDS patients with 59% CR rate, and 6/11 (55%) AML patients with a 44% CR rate in AML patients having 20-30% bone marrow blasts, for a combined 68% ORR and 53% CR rate.

Serious adverse events regardless of causality, reportedoccurring with frequency ≥5% in more than one patient in the French Phase 1b/2 MDS/AML Trial as of March 18, 2020 were: Febrilepatients who received azacitidine alone were febrile neutropenia (30%(23%), device related infection (9%pneumonia (13%), sepsis (8%(7%), lung disorder (6%), ataxia (4%), cellulitis (4%), colitis (4%), dizziness (4%), large intestine infection (4%), lung infection (4%), pneumonia (4%), septic shock (4%), subdural hematoma (4%), urinary tract infection (4% and pyrexia (7%). There have been three deaths reported by an investigator as possibly related to azacitidine: one resulting from respiratory failure, one resulting from lung disorder, and one resulting from gastrointestinal hemorrhage and septic shock.

The Phase 2 MDS/AML Post-transplant Trial

There is a significant unmet medical need for more effective therapies for patients with TP53 mutant AML and MDS following allo‑HCTallo-HCT given that the one-year post‑transplant relapse‑freepost-transplant relapse-free survival, or RFS, rate is only 30%. In the second quarter of 2019, we opened enrollment to our Phase 2 MDS/AML Post‑TransplantPost-Transplant Trial to evaluate the adverse event profile and the clinical benefit of APR‑246eprenetapopt with azacitidine on RFS in TP53 mutant MDS and AML patients who have received allo‑HCT.allo-HCT. The protocol specifies administrationprimary endpoint of 3700 mg/d APR‑246 asthe trial is the rate of RFS at 1 year. Enrollment was completed with 33 patients included in the trial.

In July 2021, we announced positive results from the trial. In the 33 patients enrolled in the trial the RFS at one-year post-transplant, the primary endpoint of the trial, was 58% and the median RFS was 12.1 months. The overall survival (OS) at 1-year post-transplant was 79% with a 6‑hour intravenous infusion daily on days 1 through 4,median OS at 19.3 months. Updated data with administrationlonger duration of 35 mg/m2/dfollow-up was presented at the 2021 American Society of Hematology (ASH) annual meeting. Results reported at ASH described a 1-year post-transplant RFS of 60% and median RFS of 12.5 months. In addition, the 1-year post-transplant OS was 79% and median OS of 20.6 months. Prior clinical trials evaluating post-transplant outcomes in TP53 mutant MDS and AML patients have a reported 1-year post-transplant RFS of ~30% and a median OS of ~5-8 months. The post-transplant regimen of eprenetapopt and azacitidine by sub‑cutaneous injection or intravenously on days 1 through 5. Patients may receive a maximum of 12 cycles ofwas well-tolerated among patients in the trial. We are in discussions with the national transplant cooperative group regarding registrational trial design for post-transplant maintenance therapy in the Phase 2 MDS/AML Post‑Transplant Trial. and are currently planning for initiation of enrollment in 2023.

As of March 18, 2020, there have been noFebruary 16, 2022, the most common (≥20%) adverse events in patients in the post-transplant trial were nausea (61%), platelet count decreased (48%), vomiting (45%), white blood cell count decreased (39%), dizziness (39%), anemia (39%), fatigue (36%), diarrhea (33%), tremor (33%), neutrophil count decreased (27%), pyrexia (24%), pruritus (24%), cough (24%), abdominal pain (21%), constipation (21%), headache (21%), decreased appetite (21%) and hypocalcemia (21%). Fatal adverse events occurred in one patient and was not reported by an investigator as related to

Clinical development in solid tumors

Phase 1/2 Clinical Trial of APR-246Eprenetapopt in R/R Gastric, Bladder and Non-Small Cell Lung Cancers

We have designed and plan to conduct acompleted enrollment in our Phase 1/2 clinical trial evaluating the adverse event profile and preliminary efficacy of APR-246eprenetapopt with anti-PD-1 therapy in advanced solid tumors including R/R gastric cancer, bladder cancer and non-small cell lung cancer. In preclinical studies reported by Ghosh and colleagues from Memorial Sloan Kettering Cancer Center at the 2019 AACR annual meeting, we have observed synergy in mouse cancer models when APR-246eprenetapopt was combined with immuno-oncology agents, including anti-PD-1. The trial will enrollenrolled both TP53 mutant and TP53 wild-type patients.

The trial enrolled 6 patients with gastric/GEJ cancer, 5 patients with bladder/urothelial cancer and we are targeting enrollment20 patients with non-small cell lung cancer (NSCLC). Enrollment of the first patient insafety lead-in cohort was completed and no dose-limiting toxicities were reported for the second half6 patients enrolled. Data from the clinical trial were presented at the European Society of 2020.

Phase 1b/2 Clinical Trial of APR-246 in Platinum-Sensitive Ovarian Cancer, or PiSARRO

As part of the early development strategy, APR‑246 was evaluated in clinical trials in ovarianMedical Oncology (ESMO) Congress 2021. Results were presented from 31 patients who had initiated treatment, including three gastric/GEJ, three bladder/urothelial cancer and this decision was based on19 NSCLC patients. In the anticipated market size and high prevalence of TP53 mutation of greater than 95% in high‑grade serous ovarian cancer, or HGSOC. In March 2014, a Phase 1b trial was initiated as a part of a combined Phase 1b/2 protocol in platinum‑sensitive HGSOC to evaluate APR‑246 with carboplatin and pegylated liposomal doxorubicin, or PLD. All patients had previously been treated with platinum‑based antineoplastic agents and all had accumulation of p53, as assessed by immunohistochemistry, or IHC, as a surrogate marker of mutant p53. Archival samples were available for 29 patients, of which 27 had DNA of sufficient quality for sequencing and all 27 were confirmed to be TP53 mutant.

The completed Phase 1b part of the trial was conducted as a dose‑escalation in 35 platinum‑sensitive and partially platinum‑sensitive patients. The primary trial objectives of the Phase 1b portion were to assess the adverse event profile of APR‑246 with carboplatin and PLD, to determine a recommended Phase 2 dose level, or RP2D, and to evaluate the pharmacokinetics of APR‑246 with carboplatin and PLD. Tumor response was a secondary objective.

The most frequently reported APR‑246‑related AEs were nausea, dizziness and fatigue, of which most were low‑grade. A limited number of APR‑246‑related grade 3+ AEs were reported, including neutropenia (37%), vomiting (14%), thrombocytopenia (9%), dizziness (6%), anemia (6%), fatigue (3%), headache (3%) and decreased appetite (3%). Serious adverse events, regardless of causality, reported in more thanbladder/urothelial cohort, one patient were: device related infection (17%)with localized TP53 mutant high-grade transitional cell bladder cancer, who relapsed following prior chemotherapy, achieved complete remission (CR) by RECIST criteria at the first response assessment at 9 weeks. In the NSCLC cohort, two patients with TP53 mutant squamous NSCLC had reductions in target lesions of 26.7% and 8.2%, vomiting (17%), febrile neutropenia (8%), infection (6%), small intestinal obstruction (6%) and thrombocytopenia (6%).

Although efficacy was not a Phase 1b trial objective, tumorrespectively, from baseline by RECIST criteria at the first response was evaluated. A 67% ORR was observed in 27 patients who were evaluable for radiological response according to RECIST 1.1, including 11%assessment at 9 weeks. With continued treatment, the NSCLC patient with complete response and 56% with partial response. In addition, an 84% ORR was observed in 25 patients who were evaluable for CA‑125 response according to Gynecologic Cancer InterGroup, or GCIG, criteria. Reductionsinitial target lesion reduction of 26.7% had further reduction in lesion size and declines in CA‑125achieved a partial respnse (PR). In addition, a second bladder cancer patient also achieved a PR. We are shown in the following figure below. All patients who were evaluable by RECIST 1.1 achievedplanning phase for a best response of stable disease or better, where stable disease indicates lack of objective response but without disease progression. The median time between prior platinum therapy and disease progression prior to enrollment in the trial, known as platinum free interval, or PFI, was 9.4 months, and 40% of patients had received more than one prior line of platinum‑based chemotherapy. Two‑thirds of patients enrolled in the trial were partially platinum‑sensitive, with PFI 6‑12 months. The remaining one‑third of patients were platinum‑sensitive, with PFI greater than 12 months. The median progression‑free survival, or PFS, was 10.2 months across all patients and was 10 months and 11.4 months in partially platinum‑sensitive and platinum sensitive patients, respectively. The median OS was 24.3 months. This was the firstfuture clinical trial to further evaluate orally-administered eprenetapopt with immunotherapy checkpoint inhibitors.

As of APR‑246February 16, 2022, the most common (≥20%) adverse events in patients receiving eprenetapopt with cytotoxic chemotherapyanti-PD-1 were dizziness (41%), nausea (38%), vomiting (32%), decreased appetite (30%), constipation (27%), fatigue (27%), dyspnea (24%), abdominal pain (22%) and we believe that the data demonstrated that the agent can be combined with carboplatin and PLD at standard doses.

Data supporting the carboplatin and PLD doublet as a treatment option in platinum‑sensitive HGSOCwhich were generated in the CALYPSO trial, a phase 3 clinical trial sponsoredreported by an international consortium of 10 cancer research organizations. The CALYPSO trial enrolled 976 patients, randomizedinvestigator as related to receive either carboplatin and PLD (48%) or carboplatin and paclitaxel (52%). All patients had received a maximum of two prior lines of chemotherapy; in the carboplatin and PLD arm, 88% had received one prior line and 12% had received two prior lines. The median interval since last chemotherapy, or therapy‑free interval, was 15.2 months in the carboplatin and PLD arm, of whom 35% had a therapy‑free interval of 6‑12 months and 65% had a therapy‑free interval in excess of 12 months. The most frequently reported AEs in the carboplatin and PLD arm included neutropenia (80%), nausea (78%), fatigue (78%), anemia (66%), constipation (55%) and vomiting (49%).study treatment. The most common grade 3+ AEs included neutropenia (35%(≥5%) serious adverse events were dyspnea (8%), thrombocytopenia (16%pulmonary embolism (5%) and anemia (8%). In the carboplatin and PLD arm PFS was reported as 11.3 months and OS as 30.7 months. Median PFS in the carboplatin and PLD arm was greater than the 9.4 months PFS in the carboplatin and paclitaxel arm (hazard ratio: 0.821, 95% CO, 0.72 – 0.94, P = 0.005). Response rates were not reported for the CALYPSO trial. Whereas the CALYPSO trial enrolled a majority of patients with treatment‑free interval exceeding 12 months, our PiSARRO Phase 1b trial enrolled a majority of patients with partially platinum‑sensitive disease which is generally recognized as a patient population with inferior treatment outcomes.

In the third quarter of 2016, enrollment commenced in the Phase 2 portion of the PiSARRO trial and concluded at 211 patients. The Phase 2 part was an open‑label, randomized, controlled multi‑center trial to assess whether patients with platinum‑sensitive recurrent HGSOC would benefit from treatment with APR‑246 in combination with carboplatin/PLD chemotherapy regimen. All patients were required to have accumulation of p53 as assessed by immunohistochemistry, a surrogate marker of mutant p53.

Patients were randomized in a 1:1 ratio to receive either APR‑246 with carboplatin and PLD or carboplatin and PLD only, with treatment to be repeated every 28 days for up to six cycles. Enrollment was concluded in April 2018. The primary endpoint for the Phase 2 part is PFS, defined as the time from registration to the time of, disease progression or relapse or death, or the date of last tumor assessment without any such event. Serious adverse events, regardless of causality, reported in more than one patient were: small intestine obstruction (4%(5%), thrombocytopenia (2%), dyspnea (2%), nausea (2%), renal impairment (2%), vomiting (2%pain (5%), abdominal pain (1%) anemia (1%(5%), constipation (1%), dehydration (1%), dizziness (1%), infectious pleural effusion (1%), large intestine perforation (1%), urinary tract infection (1%). Upon receipt of final data, we intend to conducthypotension.

Next-generation programs

APR-548

APR-548 is a subset analysis of clinical and molecular characteristics that may influence response and PFS in these patients and anticipate completing this analysis in 2020.

Phase 2 clinical trial of APR-246 in platinum-resistant ovarian cancer, or PiSARRO-R

In July 2017 we initiated an open‑label, multicenter Phase 2 trial, PiSARRO‑R, to evaluate the adverse event profile and preliminary efficacy of varying infusion regimens of APR‑246 with systemic PLD chemotherapy in platinum‑resistant HGSOC. The trial enrolled 36 patients and all patients were required to have recurrent disease with PFI between 4 weeks

and 6 months, and accumulation of p53 as assessed by immunohistochemistry, a surrogate marker of mutant p53. The majority (69%) of patients had received 2 or more prior lines of chemotherapy. Patients received either a 4500 mg/d fixed dose of APR‑246 as a 6 hour intravenous infusion (n=28, 78%), or the same or lower fixed dose over 3 or 4 hours (n=8, 22%) for four consecutive days, followed by 40 mg/m2 PLD on Day 4. The most frequently reported APR‑246‑related AEs were nausea, vomiting and dizziness. Limited APR‑246‑related grade 3+ AEs were reported, of which only anemia (n=3, 8%) was observed in more than one patient. Serious adverse events, regardless of causality, reported in more than one patient were: Intestinal obstruction (n=3, 8%) and infection (n=2, 6%). We believe the available adverse event data from the trial demonstrates that reduced duration infusion regimens with APR‑246 are feasible.

As part of the PiSARRO trials, we are collaborating with the European Network for Translational Research in Ovarian Cancer, or EUTROC, with the aim to identify predictive markers of efficacy, tolerability and clinical pharmacology.

Our second product candidate, APR-548

We are developing a next‑generation small molecule mutant p53 reactivator APR‑548,that is a novel pro‑drugunique analog of MQ that has the potential to be administeredeprenetapopt and therefore a pro-drug of MQ. APR-548 exhibits high oral bioavailability in preclinical testing and is being developed in an oral dosage form. We intend to initially develop APR‑548 in TP53 mutant hematological malignancies. We believe that an oral p53‑reactivating drug will improve patient convenience and compliance, if approved, including for patients receiving prolonged therapy in the maintenance setting.

In preclinical testing we have observed potency with APR‑548 that was superior to that of APR‑246 in a Saos‑2 osteosarcoma cell line expressing an Arg273His mutant p53 and the MIA‑PaCa‑2 pancreatic cancer cell line harboring an Arg248Trp mutant p53. The half maximal inhibitory concentration, or IC₅₀, in the Saos‑2 cell line was calculated to be 5.6 μM ± 1.0 μM (n=3) for APR‑548 and 9.5 μM ± 1.2 μM (n=37) for APR‑246, representing an approximately 40% reduction in IC₅₀ with APR‑548. In the MIA‑PaCa‑2 cell line, the IC₅₀ for APR‑548 was calculated to be 6.0 μM (n=1) versus 19 μM (n=1) for APR‑246, representing a nearly 70% reduction in IC₅₀ with APR‑548.

Reduced in vitro IC₅₀(1) of APR-548 in a p53 mutant saos-2 cell line

In xenograft studies in which mice were implanted with a breast adenocarcinoma cell line, MDA‑MB‑231‑luc, we tested the in vivo efficacy of APR‑548 when administered by twice‑daily intraperitoneal (i.p.) injection, or by twice‑daily or three times daily oral (PO) gavage. In these studies, mice received APR‑548 for three cycles where each cycle consisted of 5 consecutive days of dosing followed by 2 days without dosing. Tumor growth inhibition was measured on day 33 post‑inoculation, 3 days after the final dosing in the final cycle. In mice receiving APR‑548 via oral administration, we observed reductions in tumor weight relative to untreated control mice. Results from these studies are summarized in the following table.

In xenograft study #3 we assessed APR-548 pharmacokinetics and confirmed that circulating blood concentrations of APR-548 exceeded levels expected to be efficacious, as determined from in vitro results. Results from this xenograft study are summarized graphically in the following figure.

In in vivo studies in mouse and dog, we observed high oral bioavailability of APR-548 when dosed as either an aqueous solution or as a solid in capsules. Observed oral bioavailability ranged from 75% to greater than 99%, and with no significant effect of feeding on absorption. Results from these studies are summarized in the following table.

Based on results obtained through our preclinical in vitro and in vivo studies, we have initiated a series of studies required for IND submission. In our in vitro studies, APR‑548 has not demonstrated inhibition or induction or metabolic enzymes at concentrations up to 300 μM. Studies testing APR‑548 as an inhibitor or substrate of protein transporters have shown weak inhibition, with IC₅₀ > 150 μM, is limited to the OCT2 transporter. Additional studies have shown no significant effects when tested at 10 μM in a screen of 87 different receptors, transporters and enzymes, and no effect on the human ether‑a‑go‑go channel, or hERG, in a manual patch clamp assay at concentrations up to 100 μM. Metabolic studies have shown that APR‑548 is metabolized slowly and all metabolites produced in human cells are also produced in our mouse and dog toxicology species. Pivotal repeat‑dose and dose escalation GLP toxicology studies in multiple toxicology species have been completed and final reports are pending.

We have developed a scalable, high‑purity process for the manufacture of APR‑548 and have completed physical characterization studies to survey the landscape of APR‑548 polymorphs with properties favorable for the development of an oral formulation to be used in clinical trials.

Manufacturing

We currently contract with third parties for the manufacture of our product candidates for certain preclinical trials and clinical trial materials, including raw materials and consumables necessary for their manufacture, consistent with applicable cGMP requirements. We have assessedroutinely assess both capacity and the current clinical supply chain associated with the production of APR-246eprenetapopt and are not currently aware of any disruption to our ability to provide supply for our on-going clinical trials. We will continue to monitor and assess the potential impact of the coronavirus pandemic on our clinical trial supply chain. We intend to continue to contract for these materials in the future, including commercial

We have a manufacturing and supply agreement and quality agreement with Syngene International Private Limited for the manufacture of API. We have a service agreement with Cobra Biopharma for the clinical manufacture, labeling and packaging of formulated drug product. We have a manufacturing and supply agreements and quality agreement with Siegfried Hameln GmbH for the commercial manufacture, supply, labeling and packaging of formulated drug product.

Manufacturing clinical products is subject to extensive regulations that impose various procedural and documentation requirements, which govern record keeping, manufacturing processes and controls, personnel, quality control and quality assurance. Our contract manufacturers are required to comply with current good manufacturing practice regulations, which are regulatory requirements for the production of pharmaceuticals that will be used in humans.

Competition

The pharmaceutical and biotechnology industries generally, and the cancer drug sector specifically, are highly competitive and characterized by rapidly advancing technologies, evolving understanding of disease etiology and a strong emphasis on proprietary drugs. While we believe that our product candidates, development capabilities, experience and scientific knowledge provide us with competitive advantages, we face significant potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions. Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

There are a large number of companies developing or marketing treatments for cancer, including the indications for which we may develop product candidates. Many of the companies that we compete against or may compete against in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved drugs than we do. Small or early‑stageearly-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or that may be necessary for, our programs.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any drugs that we may develop. Our competitors also may obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before

reactivation of p53. Although there is a subset of drugs that directly target the p53 pathway, there are many cancer drugs that claim to affect the p53 pathway by upstream or complementary pathways. We are aware of molecules in development that also are being explored for p53 upregulation / activation in various stages of clinical development being tested by Actavalon, Inc., CDG Therapeutics, Inc., Cotinga Pharmaceuticals, Inc., Innovation Pharmaceuticals, Inc., MedVax Technologies, Inc., PMV Pharmaceuticals, Inc., and Senhwa Biosciences, Inc., among others. We are also aware of selective small molecule inhibitors that are designed to target the p53‑MDM2p53-MDM2 interaction in various stages of clinical development being tested by F‑HoffmanF-Hoffman La Roche Ltd and Hoffman La Roche Inc., or collectively Roche, Amgen Inc., Novartis AG, Kartos Therapeutics, Inc., Aileron Therapeutics and Daiichi Sankyo Co., Ltd. (out licensed worldwide rights to Rain Therapeutics, Inc.), including testing MDM2 inhibitors in combination with a variety of other anti‑canceranti-cancer agents. Finally, we are aware of several small molecules that are designed to inhibit the activity of Bcl‑2Bcl-2 and the related protein Mcl‑1Mcl-1 and relieve inhibition of the apoptotic cascade. Abbvie Inc.’s venetoclax has been approved in AML and chronic lymphocytic leukemia; companies with Bcl‑2Bcl-2 or Mcl‑1Mcl-1 inhibitors in various stages of preclinical or clinical development include Amgen Inc., Servier SAS, AstraZeneca Plc, Pfizer Inc. and PfizerZentalis Pharmaceuticals, Inc., among others.

If APR‑246 waseprenetapopt were approved for the indications for which we currently have ongoing clinical trials, it willwould compete with currently‑marketedcurrently-marketed drugs and willwould likely compete with other drugs that are currently in clinical development, each as discussed below.

MDS / AML

The front‑linefront-line treatments for patients with higher‑riskhigher-risk MDS in the United States are combination chemotherapy or HMAs such as Dacogen (decitabine) or Vidaza (azacitidine). We are aware of several ongoing clinical trials aimed at expanding the use of approved chemotherapy and immunomodulatory agents in higher‑riskhigher-risk MDS, as well as several new clinical programs testing novel technologies in this area, including product candidates from Abbvie Inc., argenx, Astex Pharmaceuticals, Inc., Celgene Corporation,Bristol-Myers Squibb Company, CTI BioPharma Corp., Cyclacel Pharmaceuticals, Inc., Eisai Co., Ltd., Forty SevenGilead Sciences, Inc., ALX Oncology Holdings, Inc., Shattuck Labs, Inc., Trillium Therapeutics, Inc., Karyopharm Therapeutics Inc., Onconova Therapeutics, Inc., and Takeda Pharmaceutical Company Limited.

CLL

Due to poor responses to traditional chemotherapy agents, CLL patients in the United States with high-risk 17p deletion and/or p53 mutation are typically treated with BCR inhibitors such as ibrutinib, Bcl-2 inhibitors such as venetoclax, and anti-CD20 antibodies such as rituximab. We are aware of several ongoing clinical trials aimed at expanding the use of

programs testing novel technologies in this area, including product candidates from Altor Bioscience LLC, BeiGene Ltd, Bristol-Myers Squibb Co,Co., Incyte Corp, Merck & Co Inc., Pfizer Inc., and TG Therapeutics Inc.

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Bladder cancer

The preferred treatment option for R/R bladder cancer in the United States is the anti-PD-1 antibody, pembrolizumab, Alternative regimens include other anti-PD-1 antibodies, antibodies targeting PD-L1 or CD274, FGFR inhibitors, taxanes, and topoisomerase inhibitors. We are aware of several ongoing clinical trials aimed at expanding the use of approved chemotherapy and immunomodulatory agents in R/R bladder cancer, as well as several new clinical programs testing novel technologies in this area, including product candidates from Altor Bioscience LLC, AstraZeneca Plc,, Bristol-Myers Squibb Co,Co., F. Hoffman-La Roche Ltd, and Merck & Co Inc.

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NSCLC

The preferred treatment options for R/R NSCLC depend on tumor subtype and the presence of tumor biomarkers such as genetic mutations or PD-L1 expression. Therapeutic agents include pembrolizumab, nivolumab, ipilimumab, platinum agents, taxanes, and topoisomerase inhibitors. We are aware of several ongoing clinical trials aimed at expanding the use of approved chemotherapy and immunomodulatory agents in R/R NSCLC, as well as several new clinical programs testing novel technologies in this area, including product candidates from AbbVie Inc,Inc., AstraZeneca Plc., Bayer AG, Bristol-Myers Squibb Co,Co., F. Hoffman-La Roche Ltd, Gilead Sciences Inc., Karyopharm Therapeutics Inc., Milennium Pharmaceuticals Inc., and Pfizer Inc.

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Intellectual property

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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 methods‑of‑use,methods-of-use, formulations, dosing, manufacturing processes, and crystalline solid form of one or more of our product candidates, including APR‑246,eprenetapopt, and composition of matter of our other product candidates, 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‑howknow-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets, and operate without infringing the valid and enforceable patents and other proprietary rights of third parties.

any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third parties.

Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months, and since publication of discoveries in the scientific or patent literature often lags actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications. Moreover, we may have to participate in interference proceedings declared by the United States Patent and Trademark Office, or USPTO, to determine priority of invention or in post‑grantpost-grant challenge proceedings at the USPTO or at a foreign patent office, such as inter partes review and post grant review proceedings at the USPTO and opposition proceedings at the European Patent Office, that challenge priority of invention or other features of patentability. Such proceedings could result in substantial cost, even if the eventual outcome is favorable to us. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

Patent portfolio

As of February 21, 2020,December 31, 2021, our exclusively owned patent portfolio includes fivefour U.S. issued patents, twoone pending U.S. provisional patent application, three pending U.S. nonprovisional patent applications, twofour pending international (PCT) patent applications, approximately 115104 foreign issued patents and approximately 515 pending foreign patent applications. The claims of these owned patents and patent applications are directed toward various aspects of our product candidates and research programs. Specifically, the claims of these patents and patent applications include compositions of matter for product candidates other than APR-246eprenetapopt and a crystal form of APR-246,eprenetapopt, methods-of-use, drug product formulations, dosing, diagnostics and methods of manufacture.

APR-246Eprenetapopt Method of Use Family

As of February 21, 2020,December 31, 2021, we exclusively own a patent family directed to methods‑of‑usesmethods-of-uses of APR‑246.eprenetapopt. This patent family includes one U.S. issued patent and approximately 3343 patents granted in Europe (validated in Austria, Belgium, Bulgaria, Switzerland‑Lichtenstein,Switzerland-Lichtenstein, Cyprus, Czech Republic, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Monaco, Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia and Turkey), Australia, Canada, India, and Japan. The issued patents in this family are expected to expire in 2025, not giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.

expire in 2039, not giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.

APR‑246 Process and Solid Form Family

As of February 21, 2020, we exclusively own a pending U.S. provisional patent application directed to improved processes for large scale preparation of APR‑246 and to a crystalline solid form comprising APR‑246, which was filed in 2019. This provisional patent application is not eligible to become an issued patent until, among other things, we file a non‑provisional patent application within 12 months of the filing of our provisional patent application. If we do not timely file any non‑provisional patent applications, we may lose our priority date with respect to our provisional patent application and any patent protection on the inventions disclosed in our provisional patent application. Any future U.S. patents that may issue from this provisional patent application (assuming the necessary non‑provisional patent applications are timely filed and all other applicable requirements are satisfied) are expected to expire in 2040, not giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.

Combination Therapy Of APR‑246 With A Bcl‑2 InhibitorNext-Generation Patent Family/APR-548

As of February 21, 2020,December 31, 2021, we exclusively own a patent family directed to next-generation p53 reactivators, including APR-548. In this family, we own one pending U.S. provisionalnonprovisional application and approximately 12 foreign pending applications including a European, Australian, Brazilian, Canadian, Chinese, Israeli, Indian, Japanese, Korean, New Zealand, Singapore and Taiwanese patent application, each with a filing date in 2019. In this patent family claims are directed to a methodcompositions of treatment using a combination therapymatter and methods-of-use of APR‑246 with a Bcl‑2 inhibitor. This provisional patent application is not eligible to become an issued patent until, among other things, we file a non‑provisional patent application within 12 months of the filing of our provisional patent application. If we do not timely file any non‑provisional patent applications, we may lose our priority date with respect to our provisional patent application and any patent protection on the inventions disclosed in our provisional patent application.APR-548. Any future U.S. patents that may issue from this provisional patent application (assuming the necessary non‑provisionalthese patent applications are timely filed and(assuming all other applicable requirements are satisfied) are expected to expire in 2040,2039, not giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.

the date of product approval, only one patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended.

Similar provisions are available in Europe and other non‑Unitednon-United States jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our product candidates receive FDA approval, we expect to apply for patent term extensions on patents covering those product candidates. While we intend to seek patent term extensions to any of our patents in any jurisdiction where such extensions are available, there is no guarantee that the applicable authorities, including the FDA and the USPTO in the United States, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

In addition to our reliance on patent protection for our inventions, product candidates and research programs, we also rely on trade secrets and confidentiality agreements to protect our technology, know‑howknow-how and other aspects our business that are not amenable to, or that we do not consider appropriate for, patent protection. Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual or entity during the course of the party’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual, and which are related to our current or planned business or research and development or made during normal working hours, on our premises or using our equipment or proprietary information, are our exclusive property. However, such confidentiality agreements and invention assignment agreements can be breached and we may not have adequate remedies for any such breach. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

Government Regulation

Government regulation and product approvals

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of drug products. The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

Review and approval of drugs in the United States

In the United States, the FDA approves drug products under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations. The failure to comply with applicable requirements under the FDCA and other applicable

An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following: