An update on the adalimumab biosimilar landscape following the approval of the first high-concentration biosimilar

Biosimilars can reduce healthcare costs and expand patient access to biologic therapies. Currently, eight adalimumab biosimilars have received regulatory approval from the EMA and/or the US FDA. Following recent EMA approval of the first high-concentration adalimumab biosimilar, CT-P17, this review provides a contemporary update on adalimumab biosimilars currently licensed in Europe and the USA. The totality of evidence from each clinical development program is summarized, and characteristics of each formulation and/or device that potentially affect the convenience of treatment for patients are discussed. Future perspectives are considered, including the potential impact of the FDA’s first interchangeability designation for an adalimumab biosimilar, ahead of their entry into the US marketplace in 2023.

Further Characterization of Thromboembolic Events and Association with Platelet Count Occurring during the Avatrombopag Immune Thrombocytopenia (ITP) Clinical Development Program

Background: ITP management often requires subsequent therapy beyond current first line treatments (corticosteroids or intravenous immunoglobulin). The use of thrombopoietin receptor agonists (TPO-RAs) as second-line treatment, in lieu of splenectomy or rituximab, has become more common and is supported by recent American Society of Hematology (ASH) guidelines (Neunert, 2019). The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been utilized in patients with ITP for over a decade, whereas avatrombopag (AVA) was more recently approved in June 2019. Thromboembolic events (TEEs) are not uncommon in ITP, with studies showing that up to 8% of patients experience an arterial or venous event (Sarpatwari, 2010; Vianelli, 2013). As agents that potentiate endogenous platelet production, TPO-RAs as a class may increase the risk of thromboembolism, with such events occurring in a variety of TPO-RA ITP studies. However, it is not well-understood what increased risk, over and above the inherent risk associated with ITP, TPO-RAs pose in regard to thromboembolic events (Catala-Lopez, 2015). We previously reported on the general characterization of thromboembolic events occurring during the avatrombopag ITP clinical development program (ASH 2020). Currently, we evaluate platelet counts both prior to and following the specific TEE event and report on any dosage change of avatrombopag in proximity to the TEE event. Aims: To further characterize TEEs occurring across the AVA ITP clinical development program and expand the understanding of any possible role of change in platelet count (PC) as a predictor of TEEs with AVA. Methods: 4 studies were conducted evaluating AVA in patients with ITP (two Phase 2 and two Phase 3 trials). In total, 128 patients received AVA treatment, with an average duration of exposure of ≥180 days. Occurrence of TEEs was an adverse event of special interest that was monitored closely in these studies. At the time of each TEE, the following information was collected: platelet count, AVA dose, study day of event and other medical history and lifestyle factors potentially increasing the risk for thromboembolism. PCs were also collected at each study visit as well as unplanned visits per protocol. Patients with history of arterial or venous thrombosis and more than 2 significant risk factors were excluded from the Phase 3 studies. Results: As previously reported, a total of 11 TEEs occurred in 9/128 (7%) of AVA treated patients, with one patient experiencing 3 events. No clustering of events was noted, with cerebrovascular accident being the only specific event occurring in more than one patient (occurring in 2/11 patients). In the current analysis, variability was observed in the platelet count at the time of TEE, ranging from 19,000 - 571,000/µL. Two patients experienced events at a platelet count >400,000/µL, whereas five events occurred at a PC <50,000/µL. The mean value of three PCs prior to the event in each individual patient were low (PC<130,00/µL) in 7/11 (64%), normal (PC between 130,000/µL-450,000/µL) in 4/11 (36%), and high (PC>450,000/ µL ) in 0/11 (0%) of patients. The mean value of three PCs following the event in each individual patient were low in 6/11 (55%), normal in 4/11 (36%), and high in 1/11 (9%) of patients. The change in mean PC status from prior to the event to following the event was no change in 7/11 (64%), low to normal in 2/11 (18%), low to high in 0/11 (0%), normal to low in 1/11 (9%), and normal to high in 1/11 (9%) of patients. There were no changes in AVA dose within three weeks of any TEE event. The onset of thromboembolic events ranged from study day 8 to 335, with no clear pattern materializing regarding duration of drug exposure and the onset of the TEE. Thromboembolic events were noted at daily doses of AVA ranging from 10 - 40 mg. No deaths were noted in the ITP development program. Conclusions: The TEEs noted with AVA treatment typically occurred at PCs below the upper bound of normal (450,000/µL), without relationship to drug dose and at varying number of days on study drug. No clear patterns regarding the occurrence of thromboembolic events with AVA treatment or platelet count could be determined. Clinicians should carefully monitor PC and assess the risk for thromboembolism in each individual patient treated with a TPO-RA. Figure 1 Figure 1. Disclosures Piatek: Dova: Consultancy, Speakers Bureau; Apellis: Research Funding; Alexion: Consultancy, Research Funding; Rigel: Consultancy, Research Funding. Jamieson: Sobi, Inc.: Current Employment. Kolodny: Sobi, Inc.: Current Employment.

Innovation in the discovery of the HIV-1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir

The discovery and development of fostemsavir (2), the tromethamine salt of the phosphonooxymethyl prodrug of temsavir (1), encountered significant challenges at many points in the preclinical and clinical development program that, in many cases, stimulated the implementation of innovative solutions in order to enable further progression. In the preclinical program, a range of novel chemistry methodologies were developed during the course of the discovery effort that enabled a thorough examination and definition of the HIV-1 attachment inhibitor (AI) pharmacophore. These discoveries helped to address the challenges associated with realizing a molecule with all of the properties necessary to successfully advance through development and this aspect of the program is the major focus of this retrospective. Although challenges and innovation are not unusual in drug discovery and development programs, the HIV-1 AI program is noteworthy not only because of the serial nature of the challenges encountered along the development path, but also because it resulted in a compound that remains the first and only example of a mechanistically novel class of HIV-1 inhibitor that is proving to be very beneficial for controlling virus levels in highly treatment-experienced HIV-1 infected patients.

An updated review of teriflunomide's use in multiple sclerosis

Teriflunomide, a once daily, oral disease-modifying therapy, has demonstrated consistent efficacy, safety and tolerability in patients with relapsing forms of multiple sclerosis (MS) and with a first clinical episode suggestive of MS treated up to 12 years. This review is an update to a previous version that examined data from the teriflunomide core clinical development program and extension studies. Data have since become available from active comparator trials with other disease-modifying therapies, treatment-related changes in brain volume (analyzed using structural image evaluation using normalization of atrophy) and real-world evidence including patient-reported outcomes. Initial data on the potential antiviral effects of teriflunomide in patients with MS, including case reports of patients infected with the 2019 novel coronavirus (SARS-CoV-2), are also presented.

DOP53 Pregnancy outcomes in the ozanimod clinical development program in relapsing multiple sclerosis, Ulcerative Colitis, and Crohn’s Disease

Background Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, has demonstrated efficacy in patients with relapsing multiple sclerosis (rMS) and ulcerative colitis (UC), and is being studied in Crohn’s disease (CD). S1P1-3 receptors are involved in vascular formation during embryogenesis. Within studies in the ozanimod clinical development program, female participants of childbearing potential were required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod; treatment discontinuation was required if pregnancy was confirmed. Here we review pregnancy outcomes data with ozanimod use in rMS, UC, and CD. Methods All pregnancies, including participant and partner pregnancies, in the ozanimod clinical development program with an initial diagnosis prior to a cut-off date of September 30, 2020 were assessed for pregnancy outcomes. Results At cut-off, safety data on 4131 participants were available. A total of 83 pregnancies were reported in the safety database of participants treated with ozanimod or their partners (Table). All pregnancy exposures occurred during the first trimester. Of the 60 pregnancies in ozanimod clinical trials, 9 were reported in patients with UC, and 3 in patients with CD. Participants discontinued study medication promptly except for those who elected pregnancy termination and did not discontinue study medication. Among all pregnancies in the ozanimod clinical development program, the incidence of spontaneous abortion in clinical trial participants was 15%; the rate in the general population is between 12% and 22%. The rate of preterm birth was 10.7% of live births; as reference, the global population estimate is 10.6% and the European estimate is 8.7%. No teratogenicity was observed. Outcomes in patients with UC included 2 live births that resulted in 2 full-term healthy newborns, 2 ongoing pregnancies, 2 spontaneous early losses, and 3 elective terminations. Conclusion While pregnancy should be avoided in patients on and 3 months after stopping ozanimod and clinical experience with ozanimod during pregnancy is limited, there has been no increased event of foetal abnormalities or adverse pregnancy outcomes seen with ozanimod exposure in early pregnancy.

Value-Generating Exploratory Trials in Neurodegenerative Dementias

Drug development for Alzheimer's disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof-of-concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof-of-concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab

A search of the scientific literature for Daratumumab and myeloma gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment for multiple myeloma by FDA in 2013. The high expectations have been supported and met due to a very active clinical development program, and our insight into Daratumumab’s modes of action have been expanded by a concomitant, systematic activity of translational research. The scope of this article is to point to some areas where the outcome of treatment with Daratumumab for multiple myeloma may be improved with a focus on areas such as when to initiate treatment with Daratumumab, the use of supportive treatment, duration of therapy and some general thoughts about anti-myeloma treatment as a two-step process involving initial de-bulking followed by reprogramming of the host’s immune system and immune-mediated control of myeloma.