申請上櫃 中裕愛滋新藥 拚明年在美上市 2015年05月01日 04:10 記者杜蕙蓉／台北報導 中裕新藥（4147）TMB-355靜脈注射劑型取得美國FDA突破性治療資格，預期在進行一個不到30人的三期臨床後，有機會力拚2016年在美獲准並上市下，該公司也乘勝追擊，昨（30）日正式向櫃買中心（OTC）提出上櫃申請。此外，備受矚目的TMB-355肌肉注射劑型，也預計今年4月開始募集台灣愛滋病患，進行下一階段劑量選擇的二期臨床。至於開始進行臨床前開發的第二代單株抗體（TMB-360），中裕也與台康生技（ErGenix）簽署生產合約。此計畫於去年八月獲台灣醫藥品查驗中心（CDE）選定為指標案件。連同原先的TMB-355和TMB-607，中裕目前進行的三個研發計畫都已被選定為指標案件。TMB-607為治療HIV感染的小分子蛋白酶抑制劑，此計畫由台灣生技整合育成中心（Si 2C）輔導並獲經濟部科專補助。由於此劑型具有獨特的藥動特性、安定性、且使用新賦形劑，經由與藥品查驗中心密切的諮詢和討論，目前已完成狗的GLP毒理試驗，並在台耀化學進行GMP生產，預計2015年在台灣申請臨床試驗審查（IND）。中裕表示，今年在藥物研發有顯著的進展，TMB-355在獲得美國孤兒藥資格之後，已經與FDA進行密切的討論，以利藥物儘速獲得BLA（生物製劑許可證）核准。截至2014年底，中裕的現金餘額約為新台幣15億元。該公司累計從2007年九月成立至今，虧損已超過實收資本額一半。但因2014年三月的現金增資，也帶動中裕每股淨值已由一年前的3.39元增加至8.45元。
Rilpivirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) which is used for the treatment of HIV-1 infections in treatment-naive patients. It is a diarylpyrimidine, a class of molecules that resemble pyrimidine nucleotides found in DNA. Because of its flexible chemical structure, resistance of rilpivirine is less likely to develop than other NNRTI's. FDA approved on May 20, 2011.
Rilpivirine (Edurant) (Source: http://www.aidsmap.com) Rilpivirine (Edurant), previously known as TMC278) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), developed by Johnson & Johnson/Tibotec. Rilpivirine was submitted for licensing in the United States in November 2010 and received approval for use as first-line treatment in May 2011. European marketing approval followed in November 2011. It has also been combined in a once-daily tablet (Eviplera) with Gilead's drugs tenofovir and FTC, which received marketing approval in the EU in November 2011. This combination tablet is marketed as Complera in the US. Researchers are also working on an injectable form of this drug that utilises nanoparticles and would only need to be taken once a month.1 In a 96-week randomised phase II study with over 350 treatment-naive participants, rilpivirine suppressed viral load and increased CD4 counts in similar numbers to efavirenz. This was a dose-ranging study comparing three blinded, once-daily doses of rilpivirine to open-label once-daily efavirenz (600mg), in combination with either AZT/3TC (Combivir; 76%) or tenofovir/FTC (Truvada, 24%). In a time to loss of virological response (TLOVR) analysis, 73% of patients in all three rilpivirine arms combined achieved viral loads below 50 copies/ml, compared with 71% in the efavirenz arm. Rilpivirine was active against wild-type and NNRTI-resistant virus. Very few participants (6% rilpivirine arms vs 7% efavirenz) experienced virological failure. When NNRTI resistance emerged, rates were broadly similar across all study arms. Most of the virological failures in the rilpivirine arm were related to mutations at 184V and 138K. However, patients in the rilpivirine combined arms group (all doses) had higher numbers of grade 3 to 4 adverse events (27 vs 21% EFV) and grade 3-4 laboratory abnormalities (27 vs 24% EFV arm). 2 A pooled analysis of 48-week data has been presented from two international phase III studies, ECHO and THRIVE, each of which compared rilpivirine 25mg once daily to efavirenz 600mg once daily, in combination with two nucleoside analogues, in treatment-naive individuals.3 The ECHO study randomised 690 patients, and all received a nucleoside analogue backbone of tenofovir and emtricitabine. THRIVE randomised 678 patients, with the nucleoside backbone chosen by the patient's doctor: around 60% of participants received tenofovir/FTC, 30% received AZT/3TC and 10% received abacavir/3TC. Participants had relatively low CD4 counts (a median of around 250), and high viral load (median 5 log, or 100,000 copies/ml). After 48 weeks of treatment the proportions with viral load below 50 copies/ml were almost identical (84.3% in the rilpivirine arm, 82.3% in the efavirenz arm), demonstrating non-inferiority. Virological failures (defined as two viral loads above 50 copies/ml even if viral load was suppressed again at week 48) were more frequent in the rilpivirine arm (9 vs 4.8%), and this difference was largely driven by the higher failure rate in the ECHO study (11 vs 4.4%). The statistical significance of this difference was not reported, but the difference did not vary according to nucleoside backbone, nor by baseline viral load. Patients taking rilpivirine who experienced virological failure tended to develop the E138K mutation that causes resistance to the second-line NNRTI etravirine. Half of those who experienced treatment failure while taking rilpivirine developed resistance to the drug, and of them, 90% developed resistance to etravirine too. As in the phase II studies, discontinuations due to adverse events were significantly more common in the efavirenz group (6.7 vs 2%), and central nervous system adverse events (such as dizziness and abnormal dreams) were significantly more common, occurring two to three times more often in these patients (overall frequency 38 vs 17%). Rash was also more common in efavirenz-treated patients.
References
Van t'Klooster G et al. Long-acting TMC278, a parenteral-depot formulation delivering therapeutic NNRTI concentrations in preclinical and clinical settings. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 134, 2008
Santoscoy M et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naïve patients: 96-week results of study C204. XVII International AIDS Conference, Mexico City, abstract TUAB0103, 2008
Cohen C et al. The single-tablet, fixed-dose regimen of elvitegravir/GS-9350/emtricitabine/tenofovir DF (Quad) achieves a high rate of virologic suppression and GS-9350 is an effective booster. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 58LB, San Francisco, 2010
Long-acting injectable antiretrovirals for HIV treatment and prevention Curr Opin HIV AIDS. 2013 Nov; 8(6): 565–571. TMC278 LA injection is the investigational nanosuspension formulation of RPV. The oral tablet formulation of RPV was approved in 2011, in combination with other ARV drugs, for treatment of patients with HIV-1 infection who are ARV-naive with an HIV-1 RNA level of 100 000 copies/ml or less at the start of therapy. In addition, a fixed-dose combination of RPV/TDF/TFC is approved for the same indication. Baert et al.[24▪] have published on the development of TMC278 LA nanosuspension injection. RPV free base is a stable crystalline polymorphic drug substance with very low water solubility (<0.1 mg/ml). Rilpivirine drug crystals are nanosized by a continuous wet milling process and suspended in aqueous vehicle with hydrophilic surfactant. In preclinical proof-of-concept studies, single injections of nano-formulated drug gave sustained release of RPV in plasma over 3 months in dogs and 3 weeks in mice. Further preclinical investigation of TMC278 LA 200 nmol/l injectable nanosuspension in rats and dogs included plasma pharmacokinetics, injection site concentrations and disposition to lymphoid tissues [25▪▪]. Rilpivirine plasma concentrations confirmed sustained and dose-proportional release lasting more than 2 months in rats and more than 6 months in dogs. Absolute bioavailability approached 100%, indicating complete release from the injection site. In dog, drug concentrations in the lymph nodes draining the intramuscular injection site exceeded plasma concentrations by over 100-fold 1 month after administration, while concentrations in lymphoid tissues decreased to 3-fold to 6-fold of the plasma concentrations beyond 3 months. A subsequent phase I study of TMC278 LA 300 mg/ml nanosuspension evaluated the pharmacokinetics and safety of single gluteal intramuscular or abdominal subcutaneous injections in 51 HIV-negative adult patients at doses of 200, 400 and 600 mg, or vehicle (placebo) [26]. An additional nine patients received a single 400-mg injection into deltoid muscle. Consistent with the preclinical experience, rilpivirine was slowly released from the injection site into plasma, with drug concentrations of more than 10 ng/ml for 12–26 weeks. Dose proportionality and similar plasma concentration–time profiles were observed for both subcutaneous and gluteal intramuscular injections. ISRs consisted of redness, bruising, pain and to a lesser extent, induration, and were more frequent with active drug injections versus placebo. There was a greater frequency of ISRs with subcutaneous as compared to intramuscular administration. Among intramuscular injections, gluteal injections were better tolerated than deltoid injections. There were no serious adverse events or grade 3 or 4 adverse events. Jackson et al.[27] reported results of a phase I clinical study of TMC278 LA pharmacokinetics in plasma, female genital tract and male rectum in HIV-negative adults. The investigators enrolled 20 women per dose group and evaluated single doses of 300, 600 and 1200 mg, while a sub-study enrolled six men who each received a single 600-mg dose. Blood and genital/rectal fluids were sampled to 84 days, and tissue biopsies were taken at three time points during the initial 28 days. All doses gave prolonged plasma and female genital tract and male rectum drug exposure. Among females, RPV concentrations in genital tract fluid were generally comparable to plasma drug concentrations, while vaginal tissue drug concentrations were 50% or more of the corresponding plasma measurement. In male patients, rectal fluid to blood plasma drug concentration ratios were 28 and 7% at Cmax and last observed concentration (Day 84), respectively. However, drug concentrations in rectal tissue were markedly higher and generally similar to blood plasma at study days 7 and 14. In total, these results support further evaluation of TMC278 LA as a potential PrEP strategy.
GSK1265744 is an HIV-1 INSTI and analogue of the inhibitor dolutegravir ([16,17]; ViiV Healthcare, unpublished data). The free acid of GSK1265744 has very low water solubility (<10 μg/ml). It is under clinical evaluation as both oral and long-acting injectable formulations. The drug is a subnanomolar inhibitor of HIV-1 integrase-catalyzed viral cDNA strand transfer with an in-vitro half maximal inhibitory concentration (IC50) of 0.22 and 0.34 nmol/l against HIV-1 BAL and NL432 in peripheral blood mononuclear cells, respectively. GSK1265744 is highly protein bound to serum albumin, resulting in a protein-adjusted 90% inhibitory concentration (PA-IC90) of 166 ng/ml. It has a plasma half-life of approximately 40 h following oral administration, allowing for once-daily dosing. In double-blind, placebo-controlled proof-of-concept studies of GSK1265744 monotherapy in HIV-1-infected individuals receiving 5 or 30 mg once daily for 10 days, the drug significantly reduced plasma HIV-1 RNA from baseline to day 11 versus placebo (P < 0.001); mean decrease was 2.2–2.3 log10 copies/ml, respectively [18,19]. GSK1265744 was generally well tolerated, with no clinically relevant trends in laboratory values, vital signs or electrocardiograms. A phase IIb, randomized, oral dose-ranging study is ongoing [20]. A total of 243 HIV-infected subjects were randomized to a blinded dose of GSK1265744 (10, 30 or 60 mg per day) or a control arm of efavirenz; all groups receive an investigator-selected backbone regimen of abacavir/lamivudine or TDF/FTC. After 24 weeks of triple therapy, patients randomized to GSK1265744 who achieved a plasma HIV-1 RNA level of less than 50 copies/ml enter a maintenance phase and modify their regimen to oral GSK1265744 and oral RPV 25 mg per day for an additional 72 weeks. Thus, the study evaluates a two-drug, two-class regimen of oral GSK1265744 and oral RPV for maintenance of virologic suppression. Study results will inform future trials using the long-acting injectable formulations. The long-acting injectable nanosuspension of GSK1265744 is composed of crystalline active drug, milled to a median particle size of 200 nm, along with surfactant, polymer, tonicity agent and water for injection (ViiV Healthcare, unpublished data). The nanoparticles are essentially 100% active drug in contrast to matrix nanoparticles consisting of drug encased within a polymer or lipid matrix. This enables higher drug loading into the formulation (200 mg/ml) and a reduced injection volume. Two phase I studies have reported the tolerability, safety and pharmacokinetics of GSK1265744 long-acting injection [19,21]. In a randomized, placebo-controlled, double-blinded, single-dose study, 56 HIV-uninfected adults received GSK1265744 as a gluteal intramuscular injection of 100, 200, 400 or 800 mg or an subcutaneous abdominal injection of 100, 200 or 400 mg or placebo injection vehicle. Following single intramuscular or subcutaneous injection, plasma drug concentrations increased rapidly over the first week, with sustained mean plasma concentrations above the PA–IC90 for approximately 24 weeks or longer for doses of at least 200 mg, as shown in Fig. 1. Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation [19]. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. GSK1265744 was detected in plasma to 48 weeks. Mean absorption-limited apparent terminal-phase half-life ranged from 21 to 50 days as compared to approximately 40 h following single-dose oral administration. This longer apparent half-life following injection is a result of low solubility of the nanoparticle and inherent low tissue perfusion, prompting a slow absorption rate of drug from the injectable formulation with no change in the plasma elimination half-life of the dissolved active drug. When the injectable formulation was administered as two equally divided (split dosing) injections (Cohort 4, 400 mg × 2 intramuscular and Cohort 7, 200 mg × 2 subcutaneous), total drug release was increased so that the maximum observed plasma concentration (Cmax) was greater than dose proportional and there was a more pronounced decay in drug concentrations over time. However, overall extent of exposure [area under the curve (AUC) from time zero to infinity] did not change. The most common adverse event was a self-limited injection site reaction (ISR). ISRs were generally mild, with pain and erythema at the injection site reported as the most common findings. There were no systemic serious or grade 3 to 4 adverse events.Two additional cohorts were included to evaluate drug distribution into rectal and cervicovaginal tissue to gain insight into the potential application of GSK1265744 for PrEP [22].
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