Follow-on Drugs Research Articles

Redefining Available Therapy in Oncology Accelerated Approval Decisions.

When weighing rapid approval for follow-on drugs, should @FDAOncology recognize the drugs that came before?

Impact of Manufacturing Process and Compounding on Properties and Quality of Follow-On GLP-1 Polypeptide Drugs.

The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators. Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays. Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator. This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.

HSD112 Product Entry Sequence and Priority of Follow-on Drug Use: A Case Study of Second-Generation Antipsychotics with Long-Acting Injections

HSD112 Product Entry Sequence and Priority of Follow-on Drug Use: A Case Study of Second-Generation Antipsychotics with Long-Acting Injections

Utilization, user characteristics, and adverse outcomes of insulin glargine originators and follow-on drug in patients with diabetes in the United States

Utilization, user characteristics, and adverse outcomes of insulin glargine originators and follow-on drug in patients with diabetes in the United States

A Comparative Study on Approval of Follow-on Version of Sevelamer Carbonate and Glatiramer Acetate (GA) in US, EU

Abstract: Many non-biological drugs, different in terms of their structure and mode of action, pharmacological classification, and therapeutic indication, have a common factor of structural complexity and are grouped as non-biological complex drugs (NBCDs). When an innovator drug nears the time of off-patent, different manufacturers attempt to produce its subsequent version, so the patients will have a cost-effective therapeutic equivalent. Since the innovator molecule is complex, its follow-on drug can be called its true generic version, if its bioavailability, bioequivalence and therapeutic equivalence to the innovator drug are demonstrated. However, it is observed that a case-to-case basis approach is implemented by European Medicines Agency (EMA) and Food and Drug Administration, US (USFDA) in the approval of such drugs and there is no uniformity observed between the two. : In this study, an attempt is made to study the complexity of molecules compare and understand the data requirements, and procedures adopted for the review and approval of such complex products. Therefore, drug sevelamer carbonate and glatiramer acetate are selected for the study. A methodical approach was followed. European assessment reports and drug approvals available in the orange book database of the former two regulatory agencies were studied. It is observed that the generic version of glatiramer acetate is approved as an abbreviated new drug application (ANDA) by Food and Drug Administration whereas the same was approved as the hybrid application by European Medicines Agency requiring the applicant to generate and submit more data. Thus, harmonization of the regulatory requirements for the approval of follow-on versions of such complex drugs is essential for better understanding, predictability of the regulatory process, and acceleration of the drug approval process, in the interest of patients. This will help the faster access of the drugs to the patients and allow interchangeability of the innovator drugs with its cost-effective generic version.

Harnessing the cyclization strategy for new drug discovery.

The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery. As one of the most commonly used methods in drug discovery, the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty, scaffold diversity and complexity. Such strategy could also be potentially used for the follow-on drug discovery without patent infringement. In recent years, the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases. Herein, we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds, including the proteolysis targeting chimeras (PROTAC) molecules. Particularly, we focus on four main strategies including fused ring cyclization, chain cyclization, spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation. Finally, the challenges including the synthetic intractability, relatively poor pharmacokinetics (PK) profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed. We hope this review, not exhaustive, could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.

Study of comparative efficacy of Helmintal Mini syrup (toltrazuril, moxidectin) and follow-on drugs against intestinal parasitoses of animals

The purpose of the research is comparative assessment of the efficacy and determining the optimal dosage of Helmintal Mini syrup against intestinal parasitoses of animals.Materials and methods. The studies were performed at the premises of the Lvenok veterinary clinic (Moscow). In total, the experiments involved 68 dogs and cats of various breeds, aged 2 to 11 months, infected with intestinal nematodes and coccidia. The animals were divided into test and control groups; the study drug was administered to the test, and the reference drugs were administered to the control. A drug with a toltrazuril content of 50 mg/ml and a drug with a moxidectin content of 0.6 mg/ml were used as follow-on drugs. The diagnosis and therapeutic efficacy of the drugs were confirmed based on the clinical pattern and laboratory tests by absence/presence of protozoan oocysts and helminth eggs in animal feces in laboratory studies (Fülleborn’s method); and we recorded the dynamics of clinical signs of the diseases.Results and discussion. In a comparative assessment of the efficacy of Helmintal Mini syrup with follow-on drugs, it showed the same high efficacy at coccidioses and intestinal nematodoses of animals as registered drugs containing similar active substances. The most effective and safe doses of Helmintal Mini syrup have been determined, namely, 0.5 and 1.0 ml per 1 kg of body weight.

Study of knowledge, attitude, and practice of “me-too drugs” among the prescribers in a tertiary care hospital – A cross-sectional study

Background: “Me-too drugs” are usually defined as drugs with a similar chemical structure or the identical mechanism of action as the drugs that are previously in the market. The availability of the promising first-in-class drug is generally followed by the development of drugs with similar properties, “me-too drugs,” or follow-on drugs. Aim and Objective: The aim of the study was to study the knowledge, attitude, and practice (KAP) of “me-too drugs” among prescribers in the tertiary care hospitals. Materials and Methods: A cross-sectional study was carried out using a validated questionnaire. This questionnaire assessed KAP of “me-too drugs” of the prescribers from consultants and postgraduates in the tertiary care hospitals of South India. Informed consent was taken from the study participants. The analysis of data was done using suitable statistical tests. Results: About 73% of doctors were aware that “me-too drugs” have identical chemical structure as the prototype drug in the therapeutic class. Among the participants 54% (disagreed) and 29% (agreed) that information about the benefits and safety of “me-too drugs” is inadequate. The total work experience of doctors had a maximum association (effect size = 12.6%, P = 0.0001) on knowledge. The majority of the prescribers opined that “me-too drugs” are heavily marketed than generic drugs. More drugs in a therapeutic class did not make treatment decisions difficult for the majority of the participants. Conclusion: The prescribers had very good knowledge and a positive attitude toward me-too drugs. The prescribers preferred to prescribe generic drugs over “me-too drugs.” Untoward side effects, heavy marketing and pricing of follow-on drugs were of real concern.

Extract from used Xpert MTB/RIF Ultra cartridges is useful for accurate second-line drug-resistant tuberculosis diagnosis with minimal rpoB-amplicon cross-contamination risk

Xpert MTB/RIF Ultra (Ultra) detects Mycobacterium tuberculosis and rifampicin resistance. Follow-on drug susceptibility testing (DST) requires additional sputum. Extract from the diamond-shaped chamber of the cartridge (dCE) of Ultra’s predecessor, Xpert MTB/RIF (Xpert), is useful for MTBDRsl-based DST but this is unexplored with Ultra. Furthermore, whether CE from non-diamond compartments is useful, the performance of FluoroType MTBDR (FT) on CE, and rpoB cross-contamination risk associated with the extraction procedure are unknown. We tested MTBDRsl, MTBDRplus, and FT on CEs from chambers from cartridges (Ultra, Xpert) tested on bacilli dilution series. MTBDRsl on Ultra dCE on TB-positive sputa (n = 40) was also evaluated and, separately, rpoB amplicon cross-contamination risk . MTBDRsl on Ultra dCE from dilutions ≥103 CFU/ml (CTmin <25, >“low semi-quantitation”) detected fluoroquinolone (FQ) and second-line injectable (SLID) susceptibility and resistance correctly (some SLIDs-indeterminate). At the same threshold (at which ~85% of Ultra-positives in our setting would be eligible), 35/35 (100%) FQ and 34/35 (97%) SLID results from Ultra dCE were concordant with sputa results. Tests on other chambers were unfeasible. No tubes open during 20 batched extractions had FT-detected rpoB cross-contamination. False-positive Ultra rpoB results was observed when dCE dilutions ≤10−3 were re-tested. MTBDRsl on Ultra dCE is concordant with isolate results. rpoB amplicon cross-contamination is unlikely. These data mitigate additional specimen collection for second-line DST and cross-contamination concerns.

Effect of involving certified healthcare assistants in primary care in Germany: a cross-sectional study

ObjectivesGrowing prevalence of chronic diseases and limited resources are the key challenges for future healthcare. As a promising approach to maintain high-quality primary care, non-physician healthcare professionals have been trained...

Changing Market Dynamics in the Pharmaceutical Industry: Analysis Using Data from the Last Ten Years

Using a panel dataset of 82 drugs that lost patent exclusivity in 2009-2018, we examine: (a) how brand prices change pre and post generic entry; (b) the evolution of generic share and prices in response to generic entry and (c) the market impact of follow-on products and authorized generics. We find, contrary to many prior studies, the rate of change of brand prices do moderate after generic entry; and in some cases, brands lower their price just after the onset of generic competition. Evidence does not support the proposition that brands increase prices in the period just before generic entry. We find that follow-on drugs have considerably higher generic-to-brand price ratio, and the rate of brands’ share erosion is significantly lower in markets with authorized generics. Markets with a single generic manufacturer throughout the post-entry period are found to have shallower than average decrease in prices and slower uptake of generic share.

Potential effects of increased openness in pharma: the original knowledge behind new drugs

This study seeks to determine potential changes in the degree of openness in pharmaceutical R&D by investigating where the knowledge behind new molecular entities (NMEs) comes from in terms of type of organization, geography and time. We find that the organizations granted NMEs increasingly rely on external knowledge sources but that these are increasingly shared among NME grantees. Universities are the most important indirect knowledge contributor and their relative importance has increased with time. NME grantees are increasingly relying on knowledge from different countries and the age of the knowledge sources confirms that recent NMEs are mostly follow-on drugs. This work provides evidence of the increasing openness of pharma to new knowledge sources as a means to improving the drug discovery and development process.

Trends in the costs of drugs launched in the UK between 1981 and 2015: an analysis of the launch price of drugs in five disease areas

ObjectivesTo investigate the trend in the launch price of new drugs for five common health conditions.DesignCross-sectional study using data on new drugs launched in the UK between 1981 and 2015...

Inter Partes Review: Patent Killer No More?

Inter Partes review (IPR) can efficiently invalidate drug patents and potentially convey strategic advantages to follow-on drug makers. However, recent changes in the IPR system foretell a tectonic shift in the landscape. Here we summarize these major changes and discuss the implications for the biopharmaceutical community.

A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration

Abstract Uproleselan (GMI-1271), an E-selectin antagonist, has been shown in preclinical models to disrupt activation of cell survival pathways in acute myeloid leukemia (AML), enhance chemotherapy efficacy, and improve survival. Uproleselan received FDA breakthrough therapy designation for adult relapsed/refractory AML in 2017 and Phase III studies are ongoing. In the present studies we report on the in vitro and in vivo comparative activities of an innovative high potency E-selectin antagonist, GMI-1687, a potential subcutaneously administered follow-on drug candidate to Uproleselan. The binding constant, association and dissociation rates of GMI-1687 to immobilized recombinant human (rh) E-selectin were determined by surface plasmon resonance (SPR) at 25oC. The KD of GMI-1687 was 2.4 nM, with Kon = 3 x 106 M-1s-1 and Koff = 1 x10-2 s-1. Under similar experimental conditions the KD of Uproleselan was 520 nM with Kon = 0.02 x 106 M-1s-1 and Koff = 1 x10-2 s-1. GMI-1687 was evaluated for its ability to inhibit binding of sialyl Lea to immobilized rh E-selectin. The median IC50 (n=6 independent assays) of GMI-1687 and Uproleselan in this assay was 15 and 550 nM, respectively. The in vitro activity of GMI-1687 to release adherent KG1a AML cells from E-selectin coated wells was also determined. GMI-1687 at 100 nM detached approximately 55% of adherent AML cells and was significantly different from Uproleselan at an identical concentration (38% detachment, P=0.0216). The percent bioavailability (%F) of GMI-1687 was evaluated in male Sprague-Dawley rats following intravenous (IV) and subcutaneous (SC) routes of administration at 5 mg/kg. The mean (+/- SD) SC %F for GMI-1687 was 126 +/- 3.8%. GMI-1687 also showed high bioavailability in CD-1 mice after SC administration of 0.58 mg/kg with %F = 132 +/-38. The in vivo therapeutic activity of GMI-1687 following SC administration was assessed in an acute model of inferior vena cava (IVC) thrombosis and a tumor model of AML.Immediately following the induction of a non-occlusive thrombosis via electrical stimulation (250 mAmp) of the IVC, cohorts of male C57BL/6J mice (n=5/group) were given a single SC injection of saline (0.1 mL); Uproleselan (40 mg/kg); or GMI-1687 (4 mg/kg, 0.4 mg/kg or 0.04 mg/kg), and twenty-four hrs post thrombus induction the IVC was harvested from all mice and thrombus weights were determined. Treatment with GMI-1687 decreased thrombus formation with significant inhibition at 0.04 mg/kg (92%, P&lt;0.001 compared to saline control). The inhibition of thrombus formation with GMI-1687 dosed at 0.04 mg/kg was statistically indistinguishable from Uproleselan administered SC at 40 mg/kg (97% inhibition). The therapeutic activity of SC GMI-1687 was also observed in combination with chemotherapy in a U937 tumor model. Three days post IV injection of U937 tumor cells, bone marrow ablated, female NOD/SCID mice (n=10/group) were treated with saline (0.1 mL SC QDx14); GMI-1687 (0.04 mg/kg SC QDx14) alone; cytarabine (AraC 300 mg/kg IP QDx3) + daunorubicin (DNR 3 mg/kg IV QDx1), or the combination of GMI-1687 and AraC + DNR. All treatments were well tolerated. The median survival time (MST) of mice treated with AraC + DNR was 36 days and statistically different (P&lt;0.001) to groups treated with saline (MST=22 days) or GMI-1687 alone (MST=23 days). Importantly, the therapeutic activity of AraC+DNR was significantly enhanced when combined with GMI-1687 (MST&gt;47.5 days, P=0.0153 compared to AraC+DNR alone). In summary, a highly potent innovative antagonist of E-selectin, GMI-1687, has been produced that demonstrates high bioavailability following SC administration. SC injection of GMI-1687 shows significant activity in preclinical models previously reported for parenteral administration of Uproleselan, but at approximately 250-fold lower dose. GMI-1687 is therefore well-positioned for potential use in outpatient treatment settings where an E-selectin antagonist has therapeutic relevance. IND-enabling studies with GMI-1687 are currently underway. Disclosures Peterson: GlycoMimetics: Employment, Equity Ownership. Baek:GlycoMimetics: Employment, Equity Ownership. Locatelli-Hoops:GlycoMimetics: Employment, Equity Ownership. Lee:GlycoMimetics: Employment, Equity Ownership. Deng:GlycoMimetics: Employment, Equity Ownership. Stewart:GlycoMimetics: Employment, Equity Ownership. Smith:GlycoMimetics: Employment, Equity Ownership. Fogler:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

China: The Next Pharmacy of the World?

The manufacturing success in China has not yet radiated to the pharmaceutical sector. Recently, China released a policy guideline to foster its follow-on drug industry, revealing its ambition to become a great power in the field. Here, I briefly discuss how this guideline may change the industry landscape, and its associated challenges and opportunities.

Heterogeneity of Clinical Trials for Antihypertensive Drugs in Japan: Exploratory Analysis of Confirmatory Phase III Trials Used for Marketing Approval.

The results of pivotal trials, which provide a rationale for marketing approval decisions for new drugs, are considered for various comparative purposes in postmarketing analyses. Using meta-regression analysis of 91 randomized controlled trials of 61 approved antihypertensive drugs in Japan, we show that mean baseline blood pressure (BP) of each arm was associated with predetermined entry criteria (EC), age, and trial start year (TSY). BP changes following treatment were associated with EC, subject characteristics (e.g., age, complications, baseline BP), study design (e.g., concomitant drug use), and TSY. Effect sizes were generally larger in trials for the first and second drugs in the same class than in trials for follow-on drugs. Results of pivotal trials may vary depending on many factors, suggesting possible challenges associated with the comparison of these results indirectly. Due to the heterogeneity in pivotal trials, caution should be exercised when comparing approved drugs and conducting meta-analyses retrospectively.

Access and barriers to MS care in Latin America.

Multiple sclerosis (MS), an epidemiologically emergent disorder in Latin America (LATAM), poses substantial socioeconomic challenges to a region where most countries remain as economies in development. MS is not health priority despite its economic and communitarian impact with a relatively low prevalence. MS treatments in LATAM have evolved from earlier long-term oral steroids and immunosuppression protocols, to platform disease modifying therapies (DMTs), to the current landscape with more advanced therapeutic molecules. Following FDA approval, a DMT may eventually become available in LATAM conditioned to industrial marketing interest. Most countries do not count all medications in their armamentarium. Access to therapy by the MS population in the region is low (9.5%–42.8%). Generic treatments, biosimilars, and follow-on complex non-biological drugs (CNBD) are commonly available in institutional formularies in LATAM despite their lack of supportive efficacy and safety data and reported molecular differences with the innovators. Savings to health systems thus far have been negligible. Medicine licensing agencies in LATAM, despite limitations in resources, have considerably improved their assessments by incorporating more modern criteria and methodology. Access to symptomatic management, rehabilitation procedures, and the role of patients associations are discussed.

AstraZeneca, Prilosec, and Nexium: Marketing Challenges in the Launch of a Second-Generation Drug

Tom McKillop, CEO of AstraZeneca, faced the classic quandary of large pharmaceutical firms. The firm's patent for Prilosec (active ingredient omeprazole) was expiring. Severe cost-based competition from generic drug manufacturers was inevitable. Patent expirations were nothing new for the US$15.8 billion in revenues drug firm, but Prilosec was the firm's most successful drug franchise, with global sales of US$6.2 billion. How could the company innovate its way around the generic cost-based competition and avoid the drop in revenues associated with generic drug market entry? AstraZeneca had other follow-on drugs in the pipeline—namely Nexium, an improvement on the original Prilosec molecule. Additionally, the company had the opportunity to introduce its own version of generic omeprazole, hence becoming the first mover in the generic segment, and/or introduce an OTC version of omeprazole that might tap into other markets. Ideally, AstraZeneca would like to move brand-loyal Prilosec customers to Nexium. In this market, direct-to-consumer advertising has remarkable efficacy. Classical marketing challenges of pricing and promotion need to be resolved for the Nexium launch as well as possible product and place challenges for the generic or OTC opportunity. Which combination of marketing options will allow the firm to best sustain the value of the original omeprazole innovation?The central objective of the case is to teach students how marketing variables can be used by first movers with diverse product portfolios to fend off severe price competition. These variables include pricing, promotion, product, and place (distribution) options as considered in the context of branded, generic, and OTC pharmaceutical market segments.

Private versus social incentives for pharmaceutical innovation

We provide a theoretical framework to contribute to the current debate regarding the tendency of pharmaceutical companies to direct their R&D toward marketing products that are “follow-on” drugs of already existing drugs, rather than toward the development of breakthrough drugs. We construct a model with a population of patients who can be treated with drugs that are horizontally and vertically differentiated. In addition to a pioneering drug, a new drug can be marketed as the result of an innovative process. We analyze physician prescription choices and the optimal pricing decision of an innovative firm. We also characterize the incentives of the innovative firm to conduct R&D activities, disentangling the quest for breakthrough drugs from the firm effort to develop follow-on drugs. Our results offer theoretical support for the conventional wisdom that pharmaceutical firms devote too many resources to conducting R&D activities that lead to incremental innovations.