研發產品線

UBP develops innovative therapeutic antibodies for infectious diseases, immune disorders and cancers. UB-421, an anti-CD4 antibody for treatment of HIV, is being studied in three different indications, as a single agent to substitute highly active antiretroviral therapy (HAART substitution) currently in a multi-regional phase 3 trial, and as use in combination with antiretrovirals for treatment of multi-drug resistance and for functional cure of HIV, both in phase 2 stages. UB-621, an anti-HSV antibody, is being studied for treatment of recurrent genital herpes in a phase 2 trial. UB-221, a novel anti-IgE, enters the phase 1 trial in chronic spontaneous urticaria (CSU) patients. Among three oncology antibodies currently in preclinical development stages, UB-925 is a novel anti-VEGFR2, while UB-923 and UB-926 are afucosylated versions of anti-CD20 and anti-HER2, respectively, developed from UBP’s proprietary defucosylation technology.



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UB-421創新愛滋病治療單株抗體

開發中適應症

雞尾酒藥物取代性療法、多重抗藥性愛滋病患治療、功能性治癒愛滋病。

開發階段

雞尾酒取代性療法第三期臨床試驗申請中

多重抗藥性愛滋病患治療第IIb/III臨床試驗申請中(US FDA)

功能性治癒第二期臨床試驗獲TFDA核准執行

全球盛行率/病患數

全球3670萬人感染HIV (UNAIDS 2016年統計數字)。

市場規模

全球HIV藥物市場約有240億美元(IMS Health 2016年資料)。

  • 產品簡介

    為針對愛滋病治療所開發之病毒進入阻斷單株抗體藥物。

  • 作用機制

    UB-421屬於愛滋病藥物分類上的病毒進入阻斷劑,其可作用於人體CD4細胞上CD4受體區段一之CDR2區域,藉以與愛滋病毒競爭結合位點,以阻斷愛滋病病毒侵入細胞。

  • 發展優勢

    1. 與CD4細胞結合力比HIV病毒強100倍。
    2. 可有效降低愛滋病毒量達2-3 log。
    3. 為競爭型抑制作用。
    4. 可中和多種不同亞型的病毒株,中和力寬廣。
    5. 可同時抑制「細胞接觸型(cell-to-cell)」及「非細胞接觸型(cell-free)」傳播途徑。
    6. 可活化感染病患體內的T細胞免疫性。
    7. 可單一用藥 (Monotherapy)。
  • 榮譽獎項

    1. 自1999年起研發過程榮獲五次經濟部科技專案研發補助。
    2. 獲衛福部食藥署遴選為「關鍵性指標案件」。
    3. 獲衛福部遴選為「兩岸藥品研發合作專案試辦計畫」項目。
    4. 獲衛福部/經濟部2012年「藥物科技研究發展獎」銀質獎(當年度金質獎從缺)。
    5. 獲2014年「台北生技獎研發創新獎」金獎。
    6. 獲衛福部/經濟部2014年「藥物科技研究發展獎」金質獎。
    7. 獲生策會2015年「第十二屆國家新創獎」。
    8. 獲選2017年國際反轉錄病毒與伺機性感染研討會(Conference on Retroviruses and Opportunistic Infections, CROI)以 LATE BREAKER 方式發表報告臨床二期試驗結果。

 

Q&A

1.What are the unmet needs in HIV treatment?

There are more than 30 antiretroviral (ART) drugs available in the market; yet the disease is far from being cured. ART alone cannot eradicate HIV due to the persistence of viral reservoirs and the disease can rebound following discontinuation of ART. Currently, patients infected with HIV need to take a combination of ART daily to keep the virus suppressed. The burden for patients of taking pills every day for life time and the unappreciated long-term toxicity and stigma are the unmet needs. In addition, patient’s low compliance in such a daily regimen could induce viral mutation and become resistant to the treatment and as such, there is a trend to move into less frequently administered injectable HIV drugs. New treatment options with novel mechanisms of action should be explored in order to achieve ART-free virologic remission, i.e., a functional cure.

2.What is UB-421 and its mechanisms of action?

UB-421 is an Fc-aglycosylated, non-T cell depleting and CD4-specific humanized IgG1 antibody derived from the parent murine antibody B4, which binds to discontinuous, conformational epitopes on the HIV-receptor complex, including CD4 (domain 1). Basically, UB-421 is an antibody that binds with competition edge to the site where all HIV variants attach, blocking their entry into the host cell and preventing the virus’ activity. By doing so, essentially all HIV variants including resistant viral mutants are highly sensitive to inhibition by UB-421.

In clinical trials, repeat-dose UB-421 exhibited remarkable high viral suppressing activities that are unprecedented.

UB-421 has additional immunomodulatory activity bolstering the immune system which has implications in HIV and cancer treatments.

3.Explain UBP’s technology. What makes it different from currently available treatments?

The only treatment currently available for patients with HIV is virus-targeting antiretroviral therapy (ART). While ART can minimize the viruses spread, it is not a cure. It also requires a cocktail of up to 6 different classes of drugs that must be taken daily for the rest of a patient’s lifetime. If a patient misses dosing or doesn’t take all the prescribed drugs for a period of time, their HIV can rebound and may mutate and become resistant to treatment.

UBP is developing a novel antibody in the treatment of HIV that inhibits the entry of the virus into T cells, preventing the virus’ replication. What makes our antibody unique is that it competes with HIV to bind to the same site on T cells, blocking their entry into the cell and preventing the virus’ activity without generating resistant strains. Therefore, even drug-resistant HIV strains could be treated with this host-targeting antibody.

After pre-clinical studies showing that our antibody arrested the viral spread of HIV, we continued with studies in human subjects in Phase 1, 2a and Phase 2 clinical trials with our antibody, UB-421. In our Phase 2 study, over 2-4 months, we saw that UB-421 as a single agent was highly effective at suppressing HIV levels and maintaining viral control in patients. We also saw indicators that UB-421 could reduce HIV proviral DNA as well as bolster the patient’s own immune system. This property suggests that UB-421 could also be a good candidate in developing a functional cure for HIV, a state of sustained ART-free HIV remission.

4.What were the results of the clinical trial?

The clinical results from our Phase 2 trial, which are presented in an article published in the April 18, 2019 issue of the New England Journal of Medicine, demonstrated UB-421 was a potent entry inhibitor. Using UB-421 as a single agent for the treatment of HIV-1 infected persons exhibited remarkably high viral suppression activity in all study participants that is unprecedented as compared to other ART by reducing the viral load and sustaining viral remission for at least 16 weeks.

5.Will the treatment put an HIV patient in permanent remission?

Currently, the completed clinical trials with UB-421 as a single agent are only up to 16 weeks of treatment. Yet, our preliminary data suggested a reduction of HIV proviral DNA, a marker for measuring the size of latently infected HIV reservoirs. Although this needs to be confirmed in a larger trial, we believe this is an encouraging outcome that could potentially facilitate clearance of HIV reservoirs.

Current ART acts only on the life cycle of viruses and is non-curative due to the lifelong persistence of latent viral reservoirs which remain invisible to the immune system. We have seen signs that UB-421 as a single agent can reduce the latent reservoirs of HIV infected T cells while preventing further viral transmission to uninfected cells. Taken together with other HIV studies, our results indicate that UB-421, when used in proper combination with ART, could lead to a “functional cure” in treated patients, who would have viral remission without a need of medication for a certain long period of time.

6.How does this compare to stem cell transplants?

Stem cell transplant is a medical procedure for seriously ill cancer patients, not for general HIV infected populations and it comes with a high probability of complications and risks. In addition, not all HIV patients who underwent stem cell transplants were cured; the outcome is highly variable and unpredictable. To date, there are only a few cases in the world that show the success of achieving HIV remission by stem cell transplant. Compared to a stem cell transplant procedure, our UB-421 antibody treatment is more suitable for patient populations and the risks may be significantly lower.

7.Is there a specific patient population you are targeting?

UB-421’s unique properties mean that it is applicable for almost all HIV patient populations. UB-421’s binding affinity to its target site has been shown to be the same in four studied ethnic populations. We are planning additional trials on UB-421 for a variety of patient populations including those with stably suppressed HIV and patients who are no longer responding to ART.

8.What are some of the challenges associated with using a monoclonal antibody product?

Unlike organic small molecule drugs, antibody therapies contain large immunoglobulin proteins that have to be administered by injection, either via infusion, intramuscular or subcutaneous injections. For infusion or intramuscular injection the procedure requires medical personnel at a clinic or hospital setting; while the subcutaneous injection procedure can be performed by patients at home. There are common adverse effects associated with infusion or injection, such as infusion reactions and injection site reactions.

Nevertheless, there are significant benefits with antibody drugs: 1) antibodies have long half-lives and can be administered with less frequent dosing schedule (such as administering weekly, semi-monthly or even monthly), 2) biological protein drugs have lower toxicities to liver, kidneys, etc., and 3) certain antibody drugs, such as UB-421, can exhibit beneficial immunomodulatory effects that cannot be achieved by small molecule drugs.

 

9.Where did the trial take place? Can we expect trials in the United States?

The completed Phase 1, 2a and 2 trials were conducted in Taiwan. UBP is expanding the trials with UB-421 to other countries. The phase 3 multi-regional multi-center trial with UB-421 monotherapy as substitution for ART will be conducted in Taiwan, China and Thailand. The trial for multi-drug resistance population will be conducted in the US and China. The Phase 2 functional cure trial in collaboration with NIH/NIAID is to be conducted in Taiwan but will be expanded to China and potentially in the US.

10.What next steps can we expect from UBP?

There are a number of clinical trials being planned globally in various stages. Those with regulatory approvals will be initiated in the coming months.

In addition, UBP is establishing liaison offices in Long island, NY, and subsidiary companies in China, including a clinical and regulatory development center in Shanghai, and a GMP manufacturing plant in Yangzhou. These are in preparation for the launch of several clinical trials in the US and China.

Near term, we are planning:

a) A Phase 3 trial for UB-421 as a substitution for ART in the treatment of experienced aviremic (viral load undetectable) patients. The trial will enroll 520 patients and be conducted in Taiwan, Thailand and China.

b) A Phase 2 open label, multi-center, trial for functional cure indication. It will be conducted in Taiwan and China to study the effectiveness of UB-421 in the reduction of HIV proviral DNA, a marker for measuring the size of latently infected HIV reservoirs. Our longtime collaborator at NIH/NIAID will participate in this study, applying their highly sensitive PCR assays in determining the reduction of HIV reservoirs during UB-421 treatment.

c) A Phase 2 open label, multi-center, trial for the treatment of multi-drug resistance with UB-421 as an add-on agent to the optimal background therapy. The trial will be conducted in the U.S. as well as in Asian countries.

11.What is the nature of collaboration with NIH / NIAID (National Institute of Allergy and Infectious Diseases)?

a) United Biopharma has been collaborating with Dr. Tae-Wook Chun, Chief of Immunovirology Unit and his lab at NIAID since 2015. Dr. Chun and his associates are the co-authors of the UBP’s article in the April 18 issue of NEJM.

b) Dr. Chun and his staffs performed a number of important experiments to prove UB-421’s effectiveness, such as:

1) UB-421 binds to CD4 receptors on immune T cells, the first step of blocking HIV entry, with same effectiveness in four major ethnic populations in the United States, including Caucasian, African American, Hispanic and Asian. This data is included in the April 18 issue of NEJM.

2) A single injection of UB-421 can suppress HIV growth up to 49 days in humanized mouse model.

3) UB-421 is effective in neutralizing the HIV viruses resistant to at least 4 different kinds of anti-HIV antibodies, the so called “broadly neutralizing antibodies”, currently being studied in clinical trials. One of them is VRC01, being developed by NIAID itself. This data was published in Dr. Chun’s article in the November 9, 2016 issue of NEJM.

4) UB-421 is able to reactivate latently infected HIV virus from immune T cells of HIV patients. This is the critical first step to eradicate the latent HIV reservoirs.

c) United Biopharma has signed agreement with NIAID for Dr. Chun to participate in our upcoming clinical trials for functional cure indication. He and his staffs will use the most sensitive PCR assays to measure the reduction of HIV proviral DNA in patients during the treatment with UB-421.

12.What are potential indications for UB-421?

UB-421 is developed for treatment of HIV infection potentially in four different indications:
a) Substitution – UB-421 monotherapy (single agent treatment) for substitution of ART in ART experienced patients whose viral load is stably suppressed.

b) Multi-drug resistance - combination therapy with UB-421 together with optimal background regimen of ART drugs for patients who fail treatment and show resistance to multiple classes of ART drugs.

c) First line failure – combination therapy of UB-421 and ART for patients who fail treatment from taking the first line ART.

d) Functional cure – combination therapy with UB-421 together with ART for all patients infected with HIV and have a significant size of latent HIV reservoirs.

13.How is UB-421 different from broadly neutralizing antibodies already in clinical trials?

The pipeline of United Biopharma consists of therapeutic antibody drugs in three major disease areas, infectious disease, immune disorder and oncology. In addition to UB-421, there are 5 products in various stages of development.

The virus-directing broadly neutralizing antibodies (bNAbs) target HIV-gp120 where resistance mutation can easily develop, while the host-directing UB-421 is capable of complete inhibition of infection by all variants of HIV.

No viral rebound occurred with UB-421 monotherapy, while viral resistance rapidly developed to bNAbs as a single agent. Moreover, participants enrolled to the bNAb’s trial need to be pre-screened to exclude those already showing resistance to the study drugs. HIV mutants resistant to bNAbs (e.g., VRC01, 3BNC117, 10-1074, and PGT121) are highly sensitive to the inhibition by UB-421. This data was published in the November 9, 2016 issue of NEJM.

14.How is the UB-421 antibody made and who manufactures the product?

We manufacture UB-421 at United Biopharma’s GMP facilities in Taiwan, and the production capacity will soon be expanded to UBP Greater China’s facility in Yangzhou, China. The manufacturing process has been upgraded to commercial scale, employing 2000L single-use bioreactor and state-of-the-art downstream chromatography system.

We are developing a proprietary cell line and cell culturing which can produce UB-421 at 8 to 10 grams per liter., again a record of high yield from production level aspect.

UB-621創新抗單純皰疹病毒(HSV)單株抗體

開發中適應症

反覆復發型生殖器皰疹、對抗病毒藥有抗藥性之HSV感染。

開發階段

第二期臨床試驗申請中。

全球盛行率/病患數

據WHO統計,全球50歲以下人口約有三分之二體內帶有皰疹病毒,美國地區每5人就有1人患有生殖器皰疹。

市場規模

根據GlobalData資料預估,生殖器皰疹的治療藥物市場至2023年會達到6.7億美元。

  • 產品簡介

    為一項針對單純皰疹病毒感染所開發之單株抗體藥物,提供因單純皰疹病毒感染反覆復發,或已有抗藥性之病患,更有效的療法。

  • 作用機制

    辨識第一型與第二型單純皰疹病毒表面醣蛋白gD所開發之全人源單株抗體,屬於病毒進入抑制劑。

  • 發展優勢

    1. 為目前臨床進度最快之HSV抗體藥物。
    2. 更有效的克服傳統抗病毒小分子藥物之易產生抗藥性的問題。

 

UB-221創新抗過敏(Anti-IgE)單株抗體

開發中適應症

慢性蕁麻疹(Chronic Idiopathic Urticaria)。

開發階段

臨床一期試驗。

全球盛行率/病患數

據WHO統計,2016年全球約有3.75億人患有蕁麻疹,約2/3為慢性蕁麻疹。在美國,約150萬人患有慢性蕁麻疹。

市場規模

2016年全球抗過敏藥物市場約52億美元;2016年Xolair®全球銷售額達23億美元。

  • 產品簡介

    為針對過敏病患所開發之第三代抗IgE單株抗體藥物。

  • 作用機制

    可中和引發過敏反應的IgE,也可透過CD23調控B細胞,進而阻斷IgE的生成。

  • 發展優勢

    1. 對IgE之親和力高於Xolair® 5倍以上。
    2. 除了中和IgE抗體,亦可抑制IgE的生成。

 

UB-923淋巴癌治療用生物改良性單株抗體

潛在適應症

復發或對化療有抗性之低惡度之B細胞非何杰金氏淋巴瘤、類風濕性關節炎等。

開發階段

製程開發。

盛行率/病患數

在台灣國人癌症十大死因中非何杰金氏淋巴瘤排名第九位,發生率~4/100,000人。在美國,發生率統計約20/100,000人。

市場規模

2016年全球Rituxan® 之年銷售額達73億美元。

  • 產品簡介

    為Rituximab 的生物改良性單株抗體 (biobetter)。

  • 作用機制

    拮抗B細胞表面CD20分子,藉以降低患有惡性淋巴瘤病人體內過多的B淋巴球數量,以達到改善或治療淋巴瘤之效果。

  • 發展優勢

    利用聯生藥獨創之抗體工程技術(Defuc 技術),設計表達99.99%去岩藻醣化(defucosylation)之Rituximab細胞株,具有比Rituximab高10倍的抗體依賴性細胞毒殺作用(Antibody-Dependent Cell mediated cytotoxicity;ADCC)活性,且維持原有補體依賴性細胞毒殺作用(Complement dependent cytotoxicity;CDC)活性。

 

UB-925創新抗血管生長因子受體(VEGFR2)單株抗體

潛在適應症

胃癌、大腸直腸癌、非小細胞肺癌。

開發階段

製程開發。

全球盛行率/病患數

大腸結腸癌在全球盛行癌症中佔第三位,死亡率佔第四位;台灣則為男性第一位,女性第二位 (2017年)。胃癌在所有癌症死亡率排名第二高,台灣胃癌發生率每100,000人口約10人。

市場規模

Cyramza® 約6.14億美元,比2015年成長了60%。

  • 產品簡介

    為創新抗血管生長因子第二型受體VEGFR2單株抗體藥物。

  • 作用機制

    UB-925是一個全人化單株抗體,作用在血管內皮生長因子(VEGF)第二型受體VEGFR2上,阻止VEGFR2受體活化,進而抑制腫瘤血管新生(Angiogenesis)。

  • 發展優勢

    VEGFR2在腫瘤血管中的表達與腫瘤細胞轉移相關,因此直接阻斷VEGFR2信號,可抑制腫瘤的生長與擴散。目前市面上多以VEGF抗體做為血管生成抑制劑,市場上第一個抗VEGFR2之抗體藥物為Cyramza®,與Cyramza® 相比,UB-925在體外及動物試驗結果顯示,有更佳的腫瘤抑制效果。

UB-926乳癌治療用生物改良單株抗體

潛在適應症

HER2過度表現之早期乳癌、轉移性乳癌,及 HER2過度表現之轉移性胃癌。

開發階段

製程開發。

全球盛行率/病患數

據WHO統計,每年有超過167萬人罹患乳癌。

市場規模

2016年全球HER2陽性表現乳癌市場規模約74.1億美元,2023年預估達223.5億美元。

  • 產品簡介

    為Herceptin® (trastuzumab)生物改良單株抗體藥物。

  • 作用機制

    拮抗乳癌細胞表面的HER2/neu 抗原,藉此抑制癌細胞增生,並誘發免疫細胞的細胞毒殺作用。

  • 發展優勢

    UB-926 係利用聯生藥獨創的Defuc 技術移除Trastuzumab抗體上高達97%以上之岩藻醣(Fucose),其抗體依賴性細胞毒殺作用(Antibody-dependent Cell mediated cytotoxicity; ADCC)之活性可達trastuzumab的8倍。

作用機制

UB-421屬於愛滋病藥物分類上的病毒進入阻斷劑,其可作用於人體CD4細胞上CD4受體區段一之CDR2區域,藉以與愛滋病毒競爭結合位點,以阻斷愛滋病病毒侵入細胞。

作用機制

辨識第一型與第二型單純皰疹病毒表面醣蛋白gD所開發之全人源單株抗體,屬於病毒進入抑制劑

作用機制

可中和引發過敏反應的IgE,也可透過調控B細胞表面分子CD23,進而阻斷IgE的生成

作用機制

拮抗B細胞表面CD20分子,藉以降低患有惡性淋巴瘤病人體內過多的B淋巴球數量,以達到改善或治療淋巴瘤之效果