BioCryst Pharmaceuticals Research Articles

Galidesivir, a Direct-Acting Antiviral Drug, Abrogates Viremia in Rhesus Macaques Challenged with Zika Virus

BackgroundZika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infection in humans is associated with serious neurological and reproductive complications. No antiviral or protective vaccine is yet available. Galidesivir an adenosine analog is a potent viral RNA-dependent RNA polymerase inhibitor with demonstrated broad-spectrum antiviral activity.MethodsWe have conducted four pre-clinical studies in rhesus macaques to assess the safety, antiviral efficacy and dosing strategies of galidesivir against ZIKV infection. Collectively, we have challenged 70 rhesus macaques by various routes using 1x105 TCID50of a Puerto Rican ZIKV isolate. We have evaluated galidesivir therapy administered via IM injection as early as 90 minutes and up to 72 hours after subcutaneous (SC) ZIKV challenge, and as late as 5 days after intravaginal (IVAG) challenge. In these studies, we evaluated the efficacy of a range of loading and maintence doses of galidesivir. The highest dose evaluated has been a loading dose of 100mg/kg BID followed by a maintenance dose of 25mg/kg BID for nine days. We followed multiple endpoints, including ZIKV RNA levels in plasma, urine, saliva, and cerebrospinal fluid. Immune activation, complete blood counts, chemistries and galidesivir pharmacokinetics were also monitored.ResultsGalidesivir was well-tolerated in all studies. All untreated controls developed high-level plasma viremia, and had readily detectable ZIKV RNA in CSF, saliva and urine post-infection. Animals treated in the first 24 hours after SC ZIKV challenge did not develop plasma viremia and were either negative or had significantly reduced ZIKV RNA in bodily fluids. Animals treated with galidesivir later (up to 72 hours) were partially protected; they had detectable plasma ZIKV RNA, but the onset was delayed and/or magnitude significantly reduced compared with controls. Animals infected IVAG were protected by galidesivir treatment up until day 5 after infection, with no blood viremia and significant reductions in ZIKV RNA in the CSF as compared with controls.ConclusionGalidesivir dosing in rhesus macaques was well-tolerated and offered significant protection against ZIKV infection. These results warrant continued study and clinical evaluation.Disclosures R. Taylor, BioCryst Pharmaceuticals: Employee, Salary; S. MacLennan, BioCryst: Employee, Salary; M. Leonard, BioCryst: Employee, Salary; E. Giuliano, BioCryst: Employee, Salary; A. Mathis, BioCryst Pharmaceuticals: Employee, Salary; E. Berger, BioCryst: Employee, Salary; Y. Babu, BioCryst: Employee, Salary; W. Sheridan, BioCryst Pharmaceuticals: Employee, Salary

Safety and efficacy of peramivir for influenza treatment

ObjectiveThis report presents a review of the efficacy and safety of peramivir, a neuraminidase inhibitor that was granted Emergency Use Authorization by the US Food and Drug Administration (FDA) from October 23, 2009 to June 23, 2010 during the 2009 H1N1 pandemic.MethodsLiterature was accessed via PubMed (January 2000–April 2014) using several search terms: peramivir; BCX-1812; RWJ 270201; H1N1, influenza; antivirals; and neuraminidase inhibitors. The peramivir manufacturers, Shionogi and Co Ltd and BioCryst Pharmaceuticals, were contacted to obtain unpublished data and information presented at recent scientific meetings. Information was obtained from the Centers for Disease Control and Prevention (CDC) and from US FDA websites. English-language and Japanese-language reports in the literature were reviewed and selected based on relevance, along with information from the CDC, US FDA, and the drug manufacturers.ResultsWe obtained eleven clinical trial reports of intravenous peramivir, two of which described comparisons with oseltamivir. Seven of nine other recently reported published studies was a dose–response study. Clinical reports of critically ill patients and pediatric patients infected with pandemic H1N1 described that early treatment significantly decreased mortality. Peramivir administered at 300 mg once daily in adult patients with influenza significantly reduces the time to alleviation of symptoms or fever compared to placebo. It is likely to be as effective as other neuraminidase inhibitors.ConclusionAlthough peramivir shows efficacy for the treatment of seasonal and pH1N1 influenza, it has not received US FDA approval. Peramivir is used safely and efficiently in hospitalized adult and pediatric patients with suspected or laboratory-confirmed influenza. Peramivir might be a beneficial alternative antiviral treatment for many patients, including those unable to receive inhaled or oral neuraminidase inhibitors, or those requiring nonintravenous drug delivery.

FRI0367 BCX4208 added to allopurinol increases response rates in patients with GOUT who fail to reach goal range serum uric acid on allopurinol alone: A randomized, double-blind, placebo-controlled trial

BackgroundBCX4208, a novel purine nucleoside phosphorylase inhibitor, blocks uric acid production at a step preceding xanthine oxidase and synergistically reduces serum urate concentration (sUA) in gout patients when combined with...

FRI0380 Long-term safety of BCX4208 added to allopurinol in the chronic management of GOUT: Results of a phase 2 24-week blinded safety extension and vaccine challenge study

BackgroundMost gout patients treated with 300 mg/d allopurinol do not reach the therapeutic goal range serum uric acid concentration (sUA) of <6.0 mg/dL (360 mmol/L).1 BCX4208, a purine nucleoside phosphorylase...

FRI0401 BCX4208, a novel enzyme inhibitor for chronic management of GOUT, shows a low risk of potential drug-drug interactions

BackgroundCommon comorbidities associated with gout, including obesity, hypertension, diabetes, and chronic kidney disease, may confer a greater risk of drug-drug interaction (DDI) through both polypharmacy and disease-associated alterations in drug...

Caught in the act

Femtobiology freeze‐frames crucial split seconds of chemical reactions to investigate how enzymes function. The potential prize from this knowledge could be new avenues for drug development or ways to produce clean energy.

Peramivir for the treatment of influenza

Peramivir (BioCryst Pharmaceuticals) is a novel investigational intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. Peramivir is created by a structure-based drug design and consists of a cyclopentane backbone with a positively charged guanidinyl group and lipophilic side chains. Peramivir was made available in the USA through the Emergency Investigational New Drug regulations and under an Emergency Use Authorization for hospitalized patients with known or suspected influenza during the 2009 H1N1 influenza pandemic. In trials involving ambulatory adult subjects, intravenous peramivir is safe and has a pharmacokinetic profile that supports once-daily dosing. The drug is licensed in Japan and South Korea and is currently undergoing Phase III trials in the USA. Viral resistance mechanisms to peramivir have not been fully delineated and ongoing surveillance is important. Given the serious health threat of influenza at all ages and limitations in vaccine delivery, peramivir is a promising addition to the currently limited treatment options for the treatment of severe influenza infection.

ATM cash for biotechs

In August, Somaxon Pharmaceuticals chose an alternative strategy to raise $30 million, and in June, BioCryst Pharmaceuticals of Research Triangle Park, North Carolina, used a similar tactic to raise $70 million. Both companies raised money through at-themarket (ATM) offerings, a financing tool that was not used at all in the biotech industry as recently as 2005. Since then, ATMs have been rapidly gaining favor. According to the New York-based investment bank Brinson Patrick Securities, which specializes in ATMs, by 2010 the number of ATM offerings had grown to 26 in the biotech sector (raising $184 million), nearly tripling the 9 that took place in 2009. This year there have been 15 so far. Biotechs typically raise capital by selling shares all at once in large tranches and at a fixed price, while relying on valueadding milestones, hoping that the cash can get them through to the next milestone. Instead, with an ATM offering, a company raises capital by selling shares in the open market at the prevailing price over a period of time, with the advantage that the sale of shares can be stopped or initiated at any time. Todd Wyche, founder and managing director of Brinson Patrick, thinks biotechs are shifting their approaches, using multiple financing options. “Instead of an episodic financing, relying on one or two traditional tools, we’re seeing them incorporate a more strategic kind of financing strategy,” said Wyche. Not only are ATM offerings more flexible, providing cash when needed, but they are also cheaper than traditional stock offerings in which warrants, underwriter spreads and discounts to the market price are taken into account. ATMs aren’t the perfect solution, however. One drawback is that shares have to be dribbled into the market so large amounts of capital can’t be raised quickly. But Brinson Patrick has found that issuers can sell 10–15% of the daily volume without adversely affecting the share price. The shares from an ATM offering also end up in the open market where investors may not be interested in holding them long term. Other options, such as standby equity distribution agreements offered by Yorkville Advisors of Jersey City, New Jersey, can provide the same flexibility while getting the shares into the hands of long-term investors (Nat. Biotechnol. 28, 301–302, 2010). Michael J. Nowak, managing director of Yorkville Advisors, explains that as long term– only investors, they are always interested in maintaining a strong share price for the company. “In an ATM, [bankers] do not care, since they pick up their couple of percent commission on the trade regardless of impact or price,” he adds. Brian Orelli in brief Pertuzumab to bolster Roche/Genentech’s breast cancer franchise?

Forodesine, a Purine Nucleoside Phosphorylase (PNP) Inhibitor, Shows Clinical Activity In a Phase 2 Trial In Patients with Previously Treated Chronic Lymphocytic Leukemia (CLL) – Interim Analysis

AbstractAbstract 1397 Introduction:Forodesine is a potent, specific transition-state inhibitor of the purine salvage pathway enzyme PNP. It induces apoptosis in primary CLL cells through accumulation of deoxyguanosine triphosphate. Unlike other nucleoside analogues, forodesine is not phosphorylated, is not incorporated into DNA and is not cytotoxic. Previous phase 1 and 2 studies showed clinical activity in T-cell acute lymphoblastic leukemia (i.v. forodesine) and cutaneous T-cell lymphoma (i.v. and oral). In a single institute exploratory study 5 of 13 (38%) CLL patients demonstrated anti-leukemic effects (decrease in peripheral blood malignant lymphocyte counts) with oral forodesine (200mg QD). However none of the patients achieved remission. Forodesine is absorbed via a saturable mechanism, and in a clinical pharmacology study in normal subjects, 200mg twice-daily (BID) dosing was found to partially overcome the exposure limits from once daily dosing; the 200mg BID regimen was used in the current study. Methods and Results:This is a multicenter phase II open label study. Eligible CLL patients had either failed at least 1 prior therapy (progressive disease [PD] or refractory) or were treatment-naïve provided age was >65 or ECOG 2 or 3, or unable to tolerate standard therapy. Among the 26 patients enrolled 1 was deemed ineligible (Waldenstrom's). The median age was 70 (48-92) years, 65% male and 77% had Rai Stage III/IV disease. The median duration from time to CLL diagnosis was 92.7 (8.4-243.5) months. Features of high-risk disease were del (17p) (n=6), ZAP70+ (n=13), and CD38+ (n=15). All patients had relapsed or refractory CLL with a median of 2 (1-21) prior therapies including fludarabine (76%), alkylating agents (72%), anti-CD20 monoclonal antibodies (72%) and experimental agents (36%). Interim analysis was conducted when 13 patients had been observed for ≥ 6 months: maximum duration of continuous BID forodesine therapy was 364 days. At the date of data cut-off, 20 were evaluable for response (5 were not evaluable because they had received < 8 weeks of therapy), and 12 were still on study. The revised NCI-WG (1996) criteria were used for response assessment. Partial remission was noted in 3 (15%) patients. Additionally 12 (48%) patients demonstrated stabilization of disease. PR onset was noted at 2, 6 and 6 months of therapy. Three patients discontinued due to adverse events (AEs). Serious AEs were reported in 18 patients. Individual SAEs reports included 7 cases of febrile neutropenia, 7 cases of non-neutropenic infections, pneumonia in 4, and herpes zoster in 1. Conclusion:Oral forodesine 200mg BID given continuously was generally safe and well-tolerated in previously-treated CLL patients. The overall response rate was 15%. These safety and efficacy results are particularly intriguing given the relapsed / refractory CLL population studied, which included elderly and poor performance status patients. Furthermore, we observed that, despite being a purine analog, forodesine was well tolerated with continuous daily dosing. This is particularly of interest when considering combination regimens with this new agent. Further studies of optimized dosing regimens of PNP inhibitors in CLL are warranted. These studies could include evaluation of forodesine in combination with other antileukemic agents with different mechanisms of action, in patients intolerant of or ineligible for aggressive conventional chemotherapeutic regimens, or maintenance treatment after conventional therapy. Updated results including ≥6 months follow up for all patients in the Phase II study will be presented at the meeting. Disclosures:Lyman:BioCryst Pharmaceuticals, Inc.: Employment, Equity Ownership. Cantey-Kiser:PharPoint Research, Inc.: Employment. Sheridan:BioCryst Pharmaceuticals, Inc.: Employment, Equity Ownership.

Peramivir: An Intravenous Neuraminidase Inhibitor for the Treatment of 2009 H1N1 Influenza

To review the efficacy and safety of peramivir, an unapproved neuraminidase inhibitor recently granted an Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) for the treatment of 2009 H1N1 influenza in select patients. Literature was accessed via MEDLINE (1950-April 2010) using the search terms peramivir, BCX-1812, RWJ 270201, influenza H1N1, swine influenza, and neuraminidase inhibitors. The manufacturer of peramivir, BioCryst Pharmaceuticals, was contacted for unpublished data and information presented at recent scientific meetings. Information was obtained from the Centers for Disease Control and Prevention (CDC) and FDA Web sites. The mandatory requirements for the EUA for peramivir were also consulted. Available English-language literature was reviewed and selected based on relevance, as was information from the CDC, FDA, and the drug manufacturer. The 2009 H1N1 influenza pandemic has necessitated the selective use of intravenous peramivir, an unapproved neuraminidase inhibitor. Intravenous peramivir has been studied in 4 clinical trials, 2 of which compared the drug to oseltamivir. Dose adjustments are required in pediatric patients and in those with impaired renal function. Clinicians wishing to use peramivir must request authorization from the CDC to confirm patient characteristics warranting its use and to verify the prescriber's understanding of dosing considerations and unapproved status. Peramivir has shown efficacy for the treatment of 2009 H1N1 influenza; however, it has yet to receive FDA approval. Peramivir is used in hospitalized adult and pediatric patients with suspected or laboratory-confirmed 2009 H1N1 influenza meeting specific criteria, including those unable to receive inhaled or oral neuraminidase inhibitors, those who have not responded to other neuraminidase inhibitors, or when drug delivery by a route other than intravenous is not feasible.

Forodesine [Fodosine; BioCryst Pharmaceuticals] has been granted orphan drug designation for cutaneous T cell lymphoma (CTCL) in the EU

Forodesine [Fodosine; BioCryst Pharmaceuticals] has been granted orphan drug designation for cutaneous T cell lymphoma (CTCL) in the EU

Forodesine in Patients with Refractory/Relapsed T-ALL Can Induce Prolonged Stable Remission with Minimal Toxicity before and after Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that elevates plasma 2′-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate (dGTP) levels, leading to T-cell apoptosis. It has shown promising clinical activity in patients with T-cell malignancies. Here we describe our experience with three patients with refractory or relapsed T-cell acute lymphocytic leukemia (T-ALL) who received IV forodesine before or after allogeneic transplant (pts. treated within an ongoing study from BioCryst Pharmaceuticals, Inc, Birmingham, Alabama, USA; ClinicalTrials.gov Identifier: NCT00095381).Methods: Forodesine was given at 40 mg/m2 for 5 days per week (1 cycle) for ≥6 cycles. Patients 1 and 2 received forodesine at 443 and 161 days after allogeneic hematopoietic stem cell transplantation (HSCT), respectively. Patient 3 received forodesine until 4 days before conditioning therapy prior to allogeneic HSCT.Results: Patient 1 with T-ALL was transplanted in the 2nd CR (10/10 HLA-identical sibling donor), after conditioning therapy and developed extensive wide-spread nodal relapse. After 2 weeks of forodesine, he had a very good partial response. The patient developed new-onset chronic graft-versus-host disease (GVHD) of the oral mucosa and lung during treatment. After 6 cycles, treatment was stopped and corticosteroids were given for the GVHD. This patient has been in CR3 (minimal residual disease [MRD]-negative by molecular analysis and complete donor cell chimerism) for >6 months and is no longer receiving immunosuppressives. Patient 2 is a 3-year-old girl with T-ALL who, following two induction failures, proceeded to uncomplicated 6/6 unrelated marrow transplantation in CR1. She had a bone marrow relapse 5 months after transplantation and was started on forodesine on study. After 2 weeks of treatment she achieved a CR, was MRD-negative by flow cytometry, and had 100% donor chimerism. By the middle of week 3 of treatment, she developed GVHD of the liver and was treated with cyclosporine and prednisone. Twice-weekly forodesine was restarted, and all laboratory parameters returned to normal and repeat bone marrow showed continuous CR2. This patient received forodesine twice weekly for 9 additional months and remains in CR with 100% donor chimerism for >12 months (she is no longer receiving forodesine). Patient 3, who had refractory T-ALL and disease progression shortly after relapse therapy with cladribine, cytarabine, and V16, achieved stable remission after 2 weeks of forodesine and completed 6 weeks of treatment. He then received conditioning therapy followed by an HSCT from a 10/10 HLA-identical sibling donor, and remains in CR2. No drug-specific adverse events of grade 2 or higher were seen in these patients.Conclusions: These encouraging experiences in patients with relapsed and refractory T-ALL suggest that forodesine monotherapy can be effective before and after allogeneic HSCT with minimal toxicity and without affecting potential graft-versus-leukemia effects.Forodesine Treatment in Patients before and after Allogeneic HSCTPatient No.Age/GenderDiagnosisHSCT (prior/post forodesine Tx)ResponseDisease Status128/MT-ALL, relapsePriorPRCR ongoing 215+ days23/FT-ALL, relapsePriorCRCR ongoing 398 + days327/MT-ALL, refractoryPostCRCR ongoing 180+ days

Structural Studies of the Resistance of Influenza Virus Neuramindase to Inhibitors

Zanamivir and oseltamivir, specific inhibitors of influenza virus neuraminidase, have significantly different characteristics in resistance studies. In both cases resistance is known to arise through mutations in either the hemagglutinin or neuraminidase surface proteins. A new inhibitor under development by Biocryst Pharmaceuticals, BCX-1812, has both a guanidino group, as in zanamivir, and a bulky hydrophobic group, as in oseltamivir. Using influenza A/NWS/Tern/Australia/G70C/75 (H1N9), neuraminidase variants E119G and R292K have previously been selected by different inhibitors. The sensitivity of these variants to BCX-1812 has now been measured and found in both cases to be intermediate between those of zanamivir and oseltamivir. In addition, the X-ray crystal structures of the complexes of BCX-1812 with the wild type and the two mutant neuraminidases were determined. The ligand is bound in an identical manner in each structure, with a rearrangement of the side chain of E276 from its ligand-free position. A structural explanation of the mechanism of resistance of BCX-1812, relative to zanamivir and oseltamivir in particular, is provided.

Stopped-flow studies of human aldose reductase reveal which enzyme form predominates during steady-state turnover in either reaction direction.

Progress in the aldo-keto reductase field has been quite rapid since the solution of the 3-dimensional structure of aldose reductase (ALR2) by the French group (Rondeau et al., 1992) and the Baylor group (Wilson et al., 1992), with additional contributions from Washington University School of Medicine with BioCryst Pharmaceuticals (Borhani et al., 1992) and with Dr. Quiocho’s laboratory (Wilson et al., 1993). Most recently, a definitive assignment of the active site constellation of amino acid residues and their likely roles in the catalytic mechanism was established by the collaborative efforts of researchers at Baylor, Brandeis and The Whittier Institute (Harrison et al., 1994; Bohren et al., 1994).KeywordsAldose ReductaseNucleotide BindingProgress CurveAldehyde ReductaseBurst PhaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Activities of two 9-deazaguanine analogue inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955, in vitro and in vivo.

Annals of the New York Academy of SciencesVolume 685, Issue 1 p. 248-251 Activities of Two 9-Deazaguanine Analogue Inhibitors of Purine Nucleoside Phosphorylase, CI-972 and PD 141955, in Vitro and in Vivo R. B. GILBERTSEN, R. B. GILBERTSEN Departments of ImmunopathologySearch for more papers by this authorM. K. DONG, M. K. DONG Departments of ImmunopathologySearch for more papers by this authorU. JOSYULA, U. JOSYULA Chemistry Parke-Davis Pharmaceutical Research Warner-Lambert Company Ann Arbor, Michigan 48105Search for more papers by this authorJ. C. SIRCAR, J. C. SIRCAR Departments of ImmunopathologySearch for more papers by this authorD. J. WILBURN, D. J. WILBURN Departments of ImmunopathologySearch for more papers by this authorM. C. CONROY, M. C. CONROY Departments of ImmunopathologySearch for more papers by this author R. B. GILBERTSEN, R. B. GILBERTSEN Departments of ImmunopathologySearch for more papers by this authorM. K. DONG, M. K. DONG Departments of ImmunopathologySearch for more papers by this authorU. JOSYULA, U. JOSYULA Chemistry Parke-Davis Pharmaceutical Research Warner-Lambert Company Ann Arbor, Michigan 48105Search for more papers by this authorJ. C. SIRCAR, J. C. SIRCAR Departments of ImmunopathologySearch for more papers by this authorD. J. WILBURN, D. J. WILBURN Departments of ImmunopathologySearch for more papers by this authorM. C. CONROY, M. C. CONROY Departments of ImmunopathologySearch for more papers by this author First published: June 1993 https://doi.org/10.1111/j.1749-6632.1993.tb35872.xCitations: 6 Address for correspondence: Richard B. Gilbertsen, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, Michigan 48105. Current address: Jagadish C. Sircar, Biofor Ltd., P.O. Box 629, Waverly, Pennsylvania 18471. The trivial name of 9-deazaguanine is 2-amino-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one. Designated CI-1000 by Parke-Davis Pharmaceutical Research. Designation of BioCryst Pharmaceuticals, Inc. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume685, Issue1Immunomodulating DrugsJune 1993Pages 248-251 RelatedInformation