Tribute to John C. Martin at the Twentieth Anniversary of the Breakthrough of Tenofovir in the Treatment of HIV Infections

At Bristol-Myers (BM) (1985–1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as (S)-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John’s first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (i), TDF and TAF for the treatment of hepatitis B (HBV) infections (ii), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections (iii).

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PIN9 CLINICAL PRACTICE EXPERIENCE WITH TENOFOVIR ALAFENAMIDE (TAF) FOR TREATMENT OF HEPATITIS B IN THE US

Value in Health ◽

10.1016/j.jval.2019.04.883 ◽

2019 ◽

Vol 22 ◽

pp. S196

Author(s):

M. Curry ◽

H. Bae ◽

D. Dieterich ◽

V. Ankoma-Sey ◽

R. Reddy ◽

...

Keyword(s):

Clinical Practice ◽

Hepatitis B ◽

Practice Experience ◽

The Us ◽

Tenofovir Alafenamide

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Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

Clinical Microbiology Reviews ◽

10.1128/cmr.16.4.569-596.2003 ◽

2003 ◽

Vol 16 (4) ◽

pp. 569-596 ◽

Cited By ~ 224

Author(s):

Erik De Clercq

Keyword(s):

Hepatitis B ◽

Tenofovir Disoproxil Fumarate ◽

Adefovir Dipivoxil ◽

Cowpox Virus ◽

Virus Infections ◽

Molluscum Contagiosum Virus ◽

Dna Virus ◽

Immunodeficiency Virus ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside

SUMMARY The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily).

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The Clinical Development of the First Recombinant FVIII From a Human Cell Line.

Blood ◽

10.1182/blood.v114.22.4439.4439 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4439-4439

Author(s):

Sigurd Knaub ◽

Nadezhda Zozulya

Keyword(s):

Cell Line ◽

Human Cell ◽

Safety Issue ◽

Data Monitoring Committee ◽

Human Cell Line ◽

Clinical Development ◽

Advisory Committees ◽

The Us ◽

Us Fda ◽

Recombinant Fviii

Abstract Abstract 4439 Objective In order to provide a new recombinant FVIII to the hemophilia community with potentially improved features including improved VWF binding and reduced immunogenic potential, a recombinant FVIII produced in a human cell line was developed (human-cl rhFVIII). The requirements for registration of a new recombinant FVIII in Europe are specified in a guideline. In addition, any global development plans need to be discussed with the US FDA. Methods The clinical development plan of human-cl rhFVIII follows the European guideline and the requirements as discussed with the FDA. Here we introduce the first recently started clinical trial with human-cl rhFVIII. It is a prospective, randomized, open, cross-over phase II pharmacokinetic and efficacy/safety trial in 20 patients with severe hemophilia A conducted at one center in Russia. In this trial the pharmacokinetic properties of human-cl rhFVIII will be compared with an established rFVIII product. After a wash-out phase of at least 72 hours patients will be randomly assigned to one of the two products and receive a single dose of 50 IU of FVIII/kg B.W.. Thereafter, blood will be collected at pre-specified time points over 48 hours, followed by a wash-out phase after which the second product will be administered. Subsequently, patients will be prophylactically treated for 6 months with human-cl rhFVIII to document the efficacy and safety of the product. At the end of the study, a second PK assessment with human-cl rh FVIII will be conducted. FVIII:C will be measured with validated one-stage and chromogenic assays. An “Independent Data Monitoring Committee“ will supervise the safety aspects of the trials and will perform an independent adjudication of the hemostatic efficacy assessment. Results Seven patients have been enrolled and followed for 2 – 50 exposure days on prophylactic treatment. The data of the first 7 patients indicate similar PK characteristics for human-cl rhFVIII compared to the established rFVIII. Human-cl rhFVIII was well tolerated and no safety issue has been reported yet. There were two breakthrough bleeds in target joints in two patients that were controlled with one dose of human-cl rhFVIII each. Further patients have been enrolled and updated information will be presented accordingly. Conclusion The novel human-cl rhFVIII has been successfully introduced to patients and appears to have comparable PK characteristics to a well-established marketed rFVIII and seems to be safe and well tolerated in this limited patient group. A first clinical study with human-cl rhFVIII in the US is planned to be initiated soon. Disclosures: Knaub: Octapharma AG: Employment. Zozulya:Octapharma AG: Membership on an entity's Board of Directors or advisory committees.

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Inhibition of Herpesvirus Replication by Hexadecyloxypropyl Esters of Purine- and Pyrimidine-Based Phosphonomethoxyethyl Nucleoside Phosphonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00918-08 ◽

2008 ◽

Vol 52 (12) ◽

pp. 4326-4330 ◽

Cited By ~ 11

Author(s):

Mark N. Prichard ◽

Caroll B. Hartline ◽

Emma A. Harden ◽

Shannon L. Daily ◽

James R. Beadle ◽

...

Keyword(s):

Antiviral Activity ◽

Epstein Barr Virus ◽

Hiv Infections ◽

Barr Virus ◽

Immunodeficiency Virus ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Epstein Barr ◽

Simplex Virus ◽

Ester Prodrugs

ABSTRACT Patients infected with human immunodeficiency virus (HIV) often suffer from herpesvirus infections as a result of immunosuppression. These infections can occur while patients are receiving antiretroviral therapy, and additional drugs required to treat their infection can adversely affect compliance. It would be useful to have antivirals with a broader spectrum of activity that included both HIV and the herpesviruses. We reported previously that alkoxyalkyl ester prodrugs of cidofovir are up to 3 orders of magnitude more active against herpesvirus replication and may be less toxic than the unmodified drug. To determine if this strategy would be effective for certain phosphonomethoxyethyl nucleoside phosphonates which are also active against HIV infections, the hexadecyloxypropyl (HDP) esters of 1-(phosphonomethoxyethyl)-cytosine, 1-(phosphonomethoxyethyl)-5-bromo-cytosine (PME-5BrC), 1-(phosphonomethoxyethyl)-5-fluoro-cytosine, 9-(phosphonomethoxyethyl)-2,6-diaminopurine (PME-DAP), and 9-(phosphonomethoxyethyl)-2-amino-6-cyclopropylaminopurine (PME-cPrDAP) were evaluated for activity against herpesvirus replication. The HDP esters were substantially more active than the unmodified acyclic nucleoside phosphonates, indicating that esterification with alkoxyalkyl groups increases the antiviral activity of many acyclic nucleoside phosphonates. The most interesting compounds included HDP-PME-cPrDAP and HDP-PME-DAP, which were 12- to 43-fold more active than the parent nucleoside phosphonates against herpes simplex virus and cytomegalovirus, and HDP-PME-cPrDAP and HDP-PME-5BrC which were especially active against Epstein-Barr virus. The results presented here indicate that HDP-esterified acyclic nucleoside phosphonates with antiviral activity against HIV also inhibit the replication of some herpesviruses and can extend the spectrum of activity for these compounds.

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Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.38.9.2180 ◽

1994 ◽

Vol 38 (9) ◽

pp. 2180-2182 ◽

Cited By ~ 71

Author(s):

R A Heijtink ◽

J Kruining ◽

G A de Wilde ◽

J Balzarini ◽

E de Clercq ◽

...

Keyword(s):

Tissue Culture ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Virus Infections ◽

Inhibitory Effects ◽

Duck Hepatitis ◽

B Virus ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Hepatitis B Virus Infections

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Novel Acyclic Nucleoside Phosphonate Analogues with Potent Anti-Hepatitis B Virus Activities

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.3.1177-1180.2005 ◽

2005 ◽

Vol 49 (3) ◽

pp. 1177-1180 ◽

Cited By ~ 34

Author(s):

C. Ying ◽

A. Holý ◽

D. Hocková ◽

Z. Havlas ◽

E. De Clercq ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Amino Group ◽

Wild Type ◽

Pyrimidine Base ◽

B Virus ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

ABSTRACT Novel acyclic nucleoside phosphonates with a pyrimidine base preferentially containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy or (R)-2-(phosphonomethoxy)propoxy group at C-6 selectively inhibit the replication of wild-type and lamivudine-resistant hepatitis B viruses. The activity of the most potent compounds was comparable to that of adefovir.

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Melanocortin receptors in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f38/2021.3 ◽

2021 ◽

Vol 2021 (3) ◽

Author(s):

Vanni Caruso ◽

Biao-Xin Chai ◽

Adrian J. L. Clark ◽

Roger D. Cone ◽

Alex N. Eberle ◽

...

Keyword(s):

Clinical Development ◽

Melanocortin Receptor ◽

Melanocortin Receptors ◽

Related Protein ◽

Erythropoietic Protoporphyria ◽

The Us ◽

Function Test ◽

Us Fda ◽

Diagnostic Agent ◽

Agouti Related Protein

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development.

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Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00444-06 ◽

2006 ◽

Vol 51 (2) ◽

pp. 611-615 ◽

Cited By ~ 11

Author(s):

Hyunah Choo ◽

James R. Beadle ◽

Earl R. Kern ◽

Mark N. Prichard ◽

Kathy A. Keith ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Activity ◽

Oral Bioavailability ◽

Dna Viruses ◽

B Virus ◽

Acyclic Nucleoside Phosphonates ◽

Antiviral Activities ◽

Acyclic Nucleoside

ABSTRACT Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

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