Non-oncology Indications Research Articles

Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment

The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.

Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).

Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases. The Health and Environmental Sciences Institute (HESI) - Immuno-Safety Technical Committee (ITC) organized a project to address this issue through two complementary approaches: (i) an industry survey on FIH dose selection strategies and (ii) detailed case studies for immunomodulators in oncology and non-oncology indications. Key messages from the industry survey responses highlighted a preference toward more dynamic PK/PD approaches as in vitro assays are seemingly not representative of true physiological conditions for immunomodulators. These principles are highlighted in case studies. To address the above themes, we have proposed a revised decision tree, which expands on the guidance by the IQ MABEL Working Group (Leach et al. 2021). This approach facilitates a more refined recommendation of FIH dose selection for immunomodulators, allowing for a nuanced consideration of their mechanisms of action (MOAs) and the associated risk-to-benefit ratio, among other factors.

Totally implantable venous ports in infants and children: a single-center retrospective study of indications and safety.

Totally Implantable Venous Access Devices (TIVADs) contribute significantly to the treatment progress and comfort of patients requiring long-term therapy. However, the procedure for implanting TIVADs, as well as its very presence, may be associated with complications. This study evaluates the indications, safety, and complication rates of venous port implantations in pediatric patients. It also explores factors influencing the occurrence of early and late complications post-implantation. The study included 383 pediatric patients treated at the Department of Pediatric Surgery, Traumatology, and Urology in Poznan between 2013 and 2020 who underwent 474 implantations of intravenous ports. Venous access was achieved using the Seldinger technique. Statistical analysis was performed using Statistica 13 with TIBCO and PQStat 1.8.2.156 with PQStat. Venous ports were used in 345 oncology patients requiring chemotherapy (90% of the total group) and in 38 children (10%) with non-oncology indications. There were 36 early complications (7.6%) and 18 late complications (3.8%), excluding infectious complications. The most common early, non-infectious complications included pneumothorax (15 patients; 3%) and port pocket hematoma (12 patients; 2.5%). The most common late, non-infectious complications observed were venous catheter obstruction (8 children; 1.7%) and port system leakage (5 children; 1%). Infectious complications occurred in 129 cases (27.2%). Children with a diagnosis of non-Hodgkin's lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia had a significantly higher incidence of port infections. Venous ports equipped with a polyurethane catheter, compared to systems with a silicone catheter, functioned significantly shorter. The Seldinger method of port implantation is quick, minimally invasive, and safe. The type of port, including the material of the port's venous catheter, and the underlying disease have an impact on the durability of implantable intravenous systems. The experience of the surgeon is related to the frequency of complications associated with the procedure.

The present and future of bispecific antibodies for cancer therapy.

Bispecific antibodies (bsAbs) enable novel mechanisms of action and/or therapeutic applications that cannot be achieved using conventional IgG-based antibodies. Consequently, development of these molecules has garnered substantial interest in the past decade and, as of the end of 2023, 14 bsAbs have been approved: 11 for the treatment of cancer and 3 for non-oncology indications. bsAbs are available in different formats, address different targets and mediate anticancer function via different molecular mechanisms. Here, we provide an overview of recent developments in the field of bsAbs for cancer therapy. We focus on bsAbs that are approved or in clinical development, including bsAb-mediated dual modulators of signalling pathways, tumour-targeted receptor agonists, bsAb-drug conjugates, bispecific T cell, natural killer cell and innate immune cell engagers, and bispecific checkpoint inhibitors and co-stimulators. Finally, we provide an outlook into next-generation bsAbs in earlier stages of development, including trispecifics, bsAb prodrugs, bsAbs that induce degradation of tumour targets and bsAbs acting as cytokine mimetics.

Understanding the National Institute for Health and Care Excellence Severity Premium: Exploring Its Implementation and the Implications for Decision Making and Patient Access

ObjectivesThis study aimed to evaluate the impact of the National Institute for Health and Care Excellence’s (NICE) new severity modifier, which has replaced the end-of-life (EoL) premium, on future NICE recommendations, considering past decision-making patterns. MethodsNICE technology appraisals (TAs) published between January 2020 and December 2022 were reviewed. Summary statistics were generated to assess how the new severity modifier might affect hypothetical decision making in historical TAs. ResultsA total of 138 data points were identified from 132 TAs. Although the EoL premium was applied in 46 appraisals (33%), 57 (39%) qualify for a severity-based quality-adjusted life-year (QALY) multiplier. Only 19 appraisals (14.6%) not receiving an EoL premium met the severity criteria, the majority (17) qualifying for a 1.2× multiplier. In appraisals predicted to meet the severity criteria, 45 (79%) were in oncology, making them 4.04 times (95% CI 1.91-9.02) more likely to qualify for a severity modifier than nononcology indications. Among historically EoL indications, 42 (91%) were predicted to meet the severity criteria, making them 14.8 times (95% CI 6.37-37.6) more likely to qualify for a severity modifier. ConclusionsThe new severity modifier will predominantly benefit oncology indications, continuing their previous explicit prioritization under the EoL decision modifier. However, the new severity modifier is harder to achieve and less generous; only a fraction of appraisals qualify for the highest effective £51 000 per QALY threshold. The vast majority of indications previously approved at £50 000 per QALY would now need to meet a cost-effectiveness threshold of <£36 000. This may necessitate greater pricing flexibility from manufacturers and increase the likelihood of negative recommendations.

Critical Comments by Food and Drug Administration Reviewers on Patient-Reported Outcomes in Food and Drug Administration Regulatory Submissions (2018-2021)

ObjectivesThis article examined the inclusion of patient-reported outcome (PRO) data in new drug applications (NDAs) submitted to the Food and Drug Administration (FDA) and approved from 2018 to 2021. The importance of assessing PROs, which capture patients’ perspectives on the disease and treatment experience, has been underscored by many stakeholders, including regulatory authorities. Despite the increasing inclusion of PRO assessments in registration trials, inclusion of language related to PRO results in approved product labeling varies widely. MethodsThis study examined FDA submission packages for NDAs approved by the FDA from 2018 to 2021 to identify critical reviewer comments related to PROs. Comments were identified and categorized by the type of criticism. Reviewers considered both oncology and nononcology indications. ResultsAssessment of PROs was included in 66.2% of the 210 submissions reviewed. Critical comments were identified in 45.3% of these applications; comments most commonly related to statistical analysis considerations, fit for purpose, and study design. Other categories of critical comment included data quality, lack of treatment benefit, administrative considerations, and miscellaneous issues. Differences were observed between oncology and nononcology NDAs with regard to the number and type of comments included in each of these categories. The findings highlight the importance of planning statistical analyses, establishing content validity, carefully considering study design, maximizing data quality, and demonstrating treatment benefit, among other issues. ConclusionsOverall, this study offers insight into the landscape of PRO data included in recently approved NDAs, along with recommendations for improving the quality and reporting of PROs in clinical trials.

Low serum level and chronic toxicity for methotrexate. Case Report.

Methotrexate (MTX) is a folic acid antagonist used to treat different immunological or proliferative illnesses because of its anti-proliferative and anti-inflammatory effects. MTX Toxicity is considered a severe problem. Although acute toxicity related to high-dose administration (doses ≥500 mg/m2) can be predicted based on the given dose, chronic toxicity still has no specific factors to predict it, so treatment depends on the history and symptoms of toxicity. MTX was initially used for oncology indications with high cyclic doses, then expanded to non-oncology indications with different low doses and frequencies. This significant change in doses resulted in dosing errors that contributed to MTX toxicity reports. Measures to prevent the toxicity of MTX should be implemented. A 66-year-old female patient ingested 10 mg of MTX daily for one month instead of the once-toxicity symptoms. The serum level of MTX was requested, and treatment with folinic acid was initiated until the patient improved with the discontinuation of MTX. There is limited literature about the lack the total cumulative dose, duration of intake, or serum level of MTX. All this information was provided in this case report, but drug-drug interactions were not reviewed, although aspirin and pantoprazole were identified as having interactions with methotrexate in this patient. Minimum total cumulative dose identification may help assess the toxicity risk in such patients. Low-dose MTX chronic toxicity still needs further information to guide the patient's risk of toxicity and when to initiate treatment. Safety-practical measures should be implemented to prevent such administration errors.

Bisphosphonates as Radiopharmaceuticals: Spotlight on the Development and Clinical Use of DOTAZOL in Diagnostics and Palliative Radionuclide Therapy.

Bisphosphonates are therapeutic agents that have been used for almost five decades in the treatment of various bone diseases, such as osteoporosis, Paget disease and prevention of osseous complications in cancer patients. In nuclear medicine, simple bisphosphonates such as 99mTc-radiolabelled oxidronate and medronate remain first-line bone scintigraphic imaging agents for both oncology and non-oncology indications. In line with the growing interest in theranostic molecules, bifunctional bisphosphonates bearing a chelating moiety capable of complexing a variety of radiometals were designed. Among them, DOTA-conjugated zoledronate (DOTAZOL) emerged as an ideal derivative for both PET imaging (when radiolabeled with 68Ga) and management of bone metastases from various types of cancer (when radiolabeled with 177Lu). In this context, this report provides an overview of the main medicinal chemistry aspects concerning bisphosphonates, discussing their roles in molecular oncology imaging and targeted radionuclide therapy with a particular focus on bifunctional bisphosphonates. Particular attention is also paid to the development of DOTAZOL, with emphasis on the radiochemistry and quality control aspects of its preparation, before outlining the preclinical and clinical data obtained so far with this radiopharmaceutical candidate.

Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c-KIT, and RET Anti-Targets.

FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.

HTA64 Surrogate Endpoints Used in NICE Technology Appraisals for Oncology and Non-Oncology Indications, 2022–23

HTA64 Surrogate Endpoints Used in NICE Technology Appraisals for Oncology and Non-Oncology Indications, 2022–23

Rituximab reference vs biosimilar utilization for oncology vs nononcology indications.

Limited data exist on the adoption of rituximab biosimilars vs the reference product by indication. Available data from real-world studies comparing rituximab biosimilar and reference use have focused predominantly on oncology indications. This is the first study to assess the utilization of the 3 US rituximab biosimilars vs the reference product. Comparative analysis. Deidentified real-world data of rituximab, rituximab-abbs, rituximab-pvvr, and rituximab-arrx dispensations between December 31, 2018, and February 1, 2022, were extracted using Trisus Medication Compare (The Craneware Group). The primary outcome was rituximab reference vs biosimilar utilization for oncology vs nononcology indications. Results were stratified by on-label and off-label use and treatment settings. A total of 28,025 encounters were captured for rituximab and its biosimilars across 193 facilities (rituximab: n = 23,395; biosimilars, n = 4631 [rituximab-abbs: n = 2550; rituximab-pvvr, n = 2081; rituximab-arrx: n = 0]). Rituximab reference had higher dispensations for oncology (78.4%) and nononcology (88.3%) indications than its biosimilars (21.6% and 11.7%, respectively; P < .01). The 3-year annual trends from 2019 to 2021 revealed decreased rituximab reference utilization (99.99% to 40.1%) and increased biosimilar use (0.01% to 59.9%). Most oncology dispensations were on label (94.5%), whereas most nononcology dispensations were off label (73.6%; P < .01). A higher proportion of biosimilar use was attributed to on-label indications (67.7%; off-label, 32.2%) compared with rituximab reference (58.0% vs42.0%, respectively; P < .01). Nonacademic settings showed higher biosimilar adoption than academic settings (22.2% vs 10.3%, respectively; P < .01). Real-world evidence shows an increase in rituximab biosimilar adoption over time, with higher adoption for oncology vs nononcology indications and in nonacademic settings.

Bringing cell therapy to tumors: considerations for optimal CAR binder design.

Chimeric antigen receptor (CAR)-T cells have revolutionized the immunotherapy of B-cell malignancies and are poised to expand the range of their impact across a broad range of oncology and non-oncology indications. Critical to the success of a given CAR is the choice of binding domain, as this is the key driver for specificity and plays an important role (along with the rest of the CAR structure) in determining efficacy, potency and durability of the cell therapy. While antibodies have proven to be effective sources of CAR binding domains, it has become apparent that the desired attributes for a CAR binding domain do differ from those of a recombinant antibody. This review will address key factors that need to be considered in choosing the optimal binding domain for a given CAR and how binder properties influence and are influenced by the rest of the CAR.

Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway

This study examines the Food and Drug Administration’s accelerated approval pathway and whether preapproval initiation was associated with faster conversion to traditional approval or withdrawal for drugs with nononcology indications.

US Food and Drug Administration Accelerated Approval Program for Nononcology Drug Indications Between 1992 and 2018

The US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking. To evaluate the accelerated approval program for nononcology drug indications over a period of 26 years. This retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022. The study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication. The FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication. Although the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.

Abstract 335: c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning

Abstract Engineered toxin bodies (ETBs) are next-generation immunotoxins that harbor an antibody-derived targeting domain and a cytotoxic payload derived from Shiga-like toxin-1 catalytic subunit A (SLTA). SLTA has been engineered to reduce innate immunogenicity and therefore increase the safety of ETBs whilst retaining potent cytotoxic properties. When targeted via a binding domain, SLTA is internalized and routes to the cytosol leading to irreversible ribosome inactivation and ultimately cell death. ETBs have been developed to treat a wide variety of cancers, including breast, lymphoma, multiple myeloma and PD-L1 positive solid tumors. This technology holds promise for non-oncology indications as well, particularly as a targeted and non-genotoxic conditioning regimen for hematopoietic stem cell (HSC) ablation to prepare patients for autologous stem cell transplant. c-KIT (CD117) is a well-known marker of hematopoietic stem and progenitor cells and is overexpressed in a high percentage of certain cancers including GIST, SCLC and AML. While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains. Thus, c-KIT represents a potential ETB target for both oncological and HSC transplant conditioning indications. Here we present data highlighting the in vitro potency and efficacy of CD117-targeting ETBs on cancer cell lines as well as on primary human CD34+ HSCs. CD117-targeted ETBs demonstrate exquisite specificity in vitro by killing only target positive CD34+ cells at picomolar potency while sparing the progenitors that lack CD117 expression. However, relatively low CD117 receptor levels on CD34+ HSCs prevent complete killing in vitro, limiting the observed efficacy. To overcome this challenge, an additional cytotoxic payload was conjugated to the ETB molecule to capitalize on ETBs’ unique internalization and routing properties to deliver a secondary mechanism of action. ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models. Citation Format: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg. c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 335.

Alpelisib (ALP), a breast cancer therapy, for PIK3CA-related overgrowth spectrum (PROS): A real-world data approach to a rare disease indication.

e18694 Background: PIK3CA mutations seen in cancer also drive other disease, exciting interest in repurposing oncology therapies for non-oncology indications. ALP is a PI3Kα inhibitor approved for HR+, HER2– ABC with fulvestrant. Clinical benefit of ALP in PROS, a group of rare phenotypically varied disorders driven by mutations in PIK3CA, was found in 19 pts (Venot, 2018). EPIK-P1 (NCT04285723) collected real-world data (RWD) to confirm ALP’s efficacy and safety in PROS. In the primary analysis of the primary endpoint, 12/32 pts (37.5%; 95% CI, 21.1-56.3%) with complete cases responded (≥20% reduction in the sum of target lesion volume from index/treatment [tx] start). Adverse events (AEs) and tx-related AEs were experienced by 82.5% (n = 47) and 38.6% (n = 22) of pts, respectively. The most common tx-related AE was hyperglycemia (n = 7, 12.3%). No deaths were reported (Canaud, ESMO 2021 LBA23). Methods: EPIK-P1 retrospectively abstracted data from the medical charts of pts aged ≥2 y with PROS experiencing severe/life-threatening conditions receiving ALP under compassionate use. Secondary endpoints evaluated safety and clinical benefit. Results: 57 pts were enrolled and followed for a median of 18.1 mo. No pt in the primary analysis (complete cases, n = 32) had progressive disease (PD) at wk 24; 1 pt discontinued ALP prior to wk 24 and considered a nonresponder. Of the 12 responders, median duration of response (time from first documented response to first documented PD or death due to any cause) was not estimable. Median time to censoring (date of last adequate lesion assessment) was 63.3 wk (̃14.6 mo; range, 1 d-186.7 wk); 2 pts had no further imaging assessments, 10 pts did not experience an event and tx was ongoing at data cutoff. Time to censoring was &gt; 6 mo in 7 pts and &gt; 12 mo in 6 pts. 11/20 nonresponders (55.0%) had target lesion volume reduction ranging from 0.7 to 19.6%. No pt required rescue surgery between index and wk 24. At index all pts reported ≥1 PROS-related symptom (eg, fatigue, pain). At wk 24, 82.5% (n = 47) reported symptom improvement regardless of primary analysis response status (responders, 10/12, 83.3%; nonresponders, 16/20, 80.0%). Median daily dose was 50 mg for pediatrics and 250 mg for adults. Dose reductions or interruptions were experienced by 15.8% of pts (n = 9); AEs led to dose reductions and interruptions in 3.5% (n = 2) and 10.5% (n = 6) of pts, respectively. 52 pts (91.2%) remained on tx at data cutoff; among 5 pts (8.8%) who discontinued, pt decision was the leading cause. Conclusions: RWD from EPIK-P1 demonstrate alpelisib as well tolerated, providing clinical benefit to pts with PROS regardless of response status in the primary analysis of the primary endpoint. Continued RWD collection complements planned prospective, randomized, placebo-controlled studies, facilitating access to alpelisib as an emerging pharmacologic option for PROS. Clinical trial information: NCT04285723.

Patient Preferences for Rituximab Additional Risk Minimization Measures: Results From an International Online Survey.

ObjectivePatients’ opinions are essential in optimizing risk minimization measures (RMMs) because they bring their real-life experience of disease management and medicines’ use into the regulatory assessments. The aim of the survey launched in 2018 by the European Medicines Agency, in collaboration with the Pharmacovigilance Risk Assessment Committee, was to consult targeted patient groups treated with rituximab for nononcology indications to evaluate their preferences on how to receive information on progressive multifocal leukoencephalopathy and (serious) infections. Additional RMMs such as educational materials for physicians and patients including a patient alert card (PAC) and a patient brochure (PB) are in place to minimize these risks.MethodsA question-based online survey in English created on the EU-Survey platform and disseminated primarily via relevant European patient organizations.ResultsMost patients (47 of 61) had knowledge of these potential adverse effects. Mostly, they were informed by a healthcare professional. Both a PAC and a PB were supported as useful tools to raise awareness of these adverse effects and thus minimize the potential risks among patients. Where the participants had to choose only 1 of these educational materials, 43 of them preferred a PAC, a shorted description that is always held by the patient and reaches the relevant healthcare professional when needed.ConclusionsCollecting patients’ preferences supports periodic assessment of additional RMMs and increase transparency of regulatory processes. Considering the limitations of this initial survey, further investigation is needed to generalize the results into patients’ safety outcomes.

5-Aza-4'-thio-2'-deoxycytidine, a New Orally Bioavailable Nontoxic "Best-in-Class": DNA Methyltransferase 1-Depleting Agent in Clinical Development.

DNA methyltransferase (DNMT) 1 is an enzyme that functions as a maintenance methyltransferase during DNA replication, and depletion of this enzyme from cells is considered to be a rational goal in DNA methylation-dependent disorders. Two DNMT1-depleting agents 5-aza-2'-deoxycytidine (aza-dCyd, decitabine) and 5-aza-cytidine (aza-Cyd, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia and have also been investigated for nononcology indications, such as sickle cell disease. However, these agents have several off-target activities leading to significant toxicities that limit dosing and duration of treatment. Development of more selective inhibitors of DNMT1 could therefore afford treatment of long durations at effective doses. We have discovered that 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) is as effective as aza-dCyd in depleting DNMT1 in mouse tumor models but with markedly low toxicity. In this review we describe the preclinical studies that led to the development of aza-T-dCyd as a superior DNMT1-depleting agent with respect to aza-dCyd and will describe its pharmacology, metabolism, and mechanism of action. In an effort to understand why aza-T-dCyd is a more selective DNMT1 depleting agent than aza-dCyd, we will also compare and contrast the activities of these two agents. SIGNIFICANCE STATEMENT: Aza-T-dCyd is a potent DNMT1-depleting agent. Although similar in structure to decitabine (aza-dCyd), its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off-target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs. toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases.

PRO11 Analysis of NICE Assessments for Orphan Treatments and the Role of Managed Access Agreements (MAAs)

There are challenges in the development of orphan treatments, such as small patient numbers limiting clinical trial recruitment and uncertainties related to trial outcomes. This can lead to challenges in the health technology assessment (HTA) of orphan treatments. Treatments may receive recommendation with an MAA for further data collection to address uncertainties while enabling patient access. Pricing agreements such as a patient access scheme (PAS) or commercial access agreement (CAA) may also be required. We reviewed NICE assessments of orphan treatments and the role of MAAs. The EMA website was searched to identify orphan treatments approved between January 2010 and December 2020. The NICE website was searched for assessments of these treatments. Decision outcomes and key drivers were evaluated. Between 1st January 2010 and 17th December 2020, the EMA approved 137 orphan treatments. As of 4th January 2021, 65 had undergone complete NICE HTA with 92% recommended. A greater proportion of orphan treatments for oncology indications (80%) had a completed NICE assessment compared with non-oncology indications (31%). HTAs were in progress for 18 treatments (14 non-oncology) and 42 treatments were not assessed (40 non-oncology). Only 10% of recommended treatments did not have a PAS/CAA. MAAs were required for 19% of recommended non-oncology treatments and 33% of oncology treatments were recommended through the Cancer Drugs Fund (CDF) with an MAA. Uncertainties resulting in the requirement for an MAA included the lack of long-term and/or comparative data, and uncertainties in the size of the clinical benefit and cost-effectiveness estimates. Although NICE recommended most orphan treatments assessed, an MAA (including CDF) was required for 27% of treatments as further data collection was required. Furthermore, a CAA/PAS was important for 90% of recommended treatments. Understanding of the data uncertainties identified by HTA bodies may inform the market access strategy for orphan treatments in development.

Recent developments of HDAC inhibitors: Emerging indications and novel molecules.

The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.