2016-10-01·European Journal of Drug Metabolism and Pharmacokinetics4区 · 医学
Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure
4区 · 医学
作者: Pan-Zhou, Xin-Ru ; Mayes, Benjamin A. ; Rashidzadeh, Hassan ; Gasparac, Rahela ; Smith, Steven ; Bhadresa, Sanjeev ; Gupta, Kusum ; Cohen, Marita Larsson ; Bu, Charlie ; Good, Steven S. ; Moussa, Adel ; Rush, Roger
IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.
2016-05-01·Human & Experimental Toxicology4区 · 医学
Single- and repeat-dose toxicity of IDX14184, a nucleotide prodrug with antiviral activity for hepatitis C viral infection, in mice, rats, and monkeys
4区 · 医学
作者: Luo, S. ; Rush, R. ; Standring, D.
The single- and repeat-dose toxicity profile of IDX14184, a novel guanosine nucleotide prodrug with antiviral activity against hepatitis C viral infection, was characterized following once daily oral administration for durations up to 13, 26, and 32 weeks in mouse, rat, and cynomolgus monkey, respectively. The heart, liver, kidney, skeletal muscles, and lower gastrointestinal tract (cecum, colon, and/or rectum) were identified as the primary toxicity targets in these nonclinical species. The mouse was relatively insensitive to IDX14184-induced cardiac toxicity and hepatotoxicity. The rat was very sensitive to IDX14184-induced skeletal muscle, liver, heart, and lower gastrointestinal tract toxicity but relatively insensitive to kidney toxicity. The monkey is a good animal species to detect IDX14184-induced toxicity in the cardiac and skeletal muscles, and in the liver and kidney, but not lower gastrointestinal tract toxicity. The toxicity profile of IDX14184 was most appropriately characterized in rats and monkeys. The conduct of a series of cardiac size and function assessments during a non-rodent toxicology study using echocardiography proved great utility in this work. IDX14184 clinical development was eventually terminated due to suboptimal efficacy and regulatory concerns on potential heart and kidney injury in patients, as seen with a different guanosine nucleotide prodrug, BMS-986094.
2015-04-17·Organic Process Research & Development
Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture
作者: Mayes, Benjamin A. ; Wang, Jingyang ; Arumugasamy, Jeevanandam ; Arunachalam, Kannan ; Baloglu, Erkan ; Bauer, David ; Becker, Alan ; Chaudhuri, Narayan ; Glynn, Roberta ; Latham, G. Mark ; Li, Jie ; Lim, Jinsoo ; Liu, Jia ; Mathieu, Steve ; McGarry, F. Patrick ; Rosinovsky, Elodie ; Soret, Adrien F. ; Stewart, Alistair ; Moussa, Adel
A scalable process is described for the synthesis of 2'-C-methylguanosine-5'-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2',3'-hydroxyls of 2'-C-methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous-organic solvents presented addnl. processing challenges. The use of reverse phase chromatog. for the final purification was eliminated by the development of a dual liquid-liquid extraction protocol, which removed both non-polar and polar impurities while maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to <10 ppm in the final product. This process produced 20 kg of drug substance in 59% overall yield, with >99% purity in the requisite 1:1 diastereomeric ratio.
Welcome to this week's Chutes & Ladders, our roundup of hirings, firings and retirings throughout the industry. Please send the good word—or the bad—from your shop to Max Bayer or Gabrielle Masson, and we will feature it here at the end of each week.
After 4-year run, Cerevel CEO set to step down
Cerevel CEO Tony Coles, M.D., will be handing over the reins to Bain Capital’s Ron Renaud on June 12. Renaud, who is Coles’ longtime friend, will become the neuroscience biotech’s new president, CEO and board member, while Coles will maintain his role as chair.
Coles took on the head role of the Pfizer spinout back in 2019, guiding Cerevel’s public market debut in 2020 and overseeing pipeline development of several neurological diseases, such as Parkinson’s, epilepsy and schizophrenia.
Renaud, a current partner at Bain Capital—which has invested heavily in Cerevel—comes in at a critical inflection point. The company anticipates seven data readouts in the next 12 to 18 months, pinning hopes specifically on emraclidine, which is currently being evaluated in a phase 2 trial in patients with schizophrenia who experience psychosis. Renaud said Cerevel is planning for a commercial launch of the asset.
The incoming CEO has held the top job at two biotechs over the last few decades. He led mRNA-based Translate Bio for seven years until late 2021, when the company was acquired by Sanofi for $3.2 billion. Before that, he served as president and CEO of Idenix Pharmaceuticals, which was acquired by Merck & Co. for $3.85 billion in 2014. The executive has also served as chair of several biotechs such as Atara Biotherapeutics, Ikena Oncology and Axial Biotherapeutics, among others. Fierce Biotech
Day One revamps C-suite
Day One Pharmaceuticals
Day One’s co-founder and chief medical officer, Samuel Blackman, M.D., Ph.D., has been with the company, since, well, day one. And while he’s sticking around, he’s moving outside of the executive team to head research and development for the company, guiding earlier scientific research. He’d been Day One’s CMO since November 2022.
He’ll be replaced by Raphaël Rousseau, M.D., Ph.D., who recently served as chief medical officer at Neogene Therapeutics and Gritstone Bio. Before leading clinical development at biotechs, Rousseau was the pediatric franchise head at Genentech, creating the innovative pediatric drug development team which in part incorporated kids into all stages of the development process for new oncology treatments.
In addition to revamping R&D leadership, Day One has named Lauren Merendino as chief commercial officer. She’s a fellow Genentech alum herself, having previously been the VP of neurological rare diseases before becoming commercial chief at Myovant Sciences. Release
Former Iovance CEO and VC partner jumps to Lassen
Maria Fardis, Ph.D., evidently couldn’t resist the opportunity to return to a biotech C-suite, being named CEO of Lassen Therapeutics. She’d spent less than two years as a venture partner at Frazier Life Sciences after leading Iovance Biotherapeutics for more than five years.
While at Iovance, she helped grow the company’s market cap twentyfold, from $200 million to $4 billion, by growing the company’s pipeline of tumor-infiltrating lymphocytes. The company now has more than a half-dozen treatment combos in mid- to late-stage trials, including two ongoing pivotal trials for its lead asset, lifileucel.
She’s also had experience developing breakthrough therapies that have caught the eye of Big Pharma, namely Imbruvica and Calquence. Fardis was chief of oncology operations and alliances at Pharmacyclics where she managed the partnership between the biotech and Janssen, which licensed what ultimately became Imbruvica. She then moved to Acerta where she oversaw the clinical development program for acalabrutinib (now Calquence) and was part of the team that conducted due diligence ahead of AstraZeneca’s $4 billion stake in the company. Release
> Founding President and CEO of AvroBio Geoff MacKay is leaving to join an early-stage venture, the company announced this week. MacKay has led the company for the last eight years and will be replaced on an interim basis by current CFO Erik Ostrowski. Release
> Women’s health-focused ObsEva has landed on a new CEO, naming Fabien de Ladonchamps for the job. He’s been a member of the company’s executive team for almost 10 years, having previously served as chief administrative officer and interim CFO. Release
> After co-founder and CEO Masoud Tavazoie, M.D., Ph.D, recently stepped down, Inspirna has named a new leader, calling on Usman “Oz” Azam, M.D., to take the chief executive reins. Azam was previously head of cell and gene therapies at Novartis before taking CEO roles at Empyrean Neuroscience and Tmunity. Release
> Ariella Kelman, M.D., is moving into the C-suite at Biora Therapeutics, accepting the chief medical officer job. She most recently was SVP of clinical development at HI-Bio after more than 15 years at Genentech. Release
> Kazia Therapeutics’ CEO and managing director James Garner has resigned after more than seven years helming the oncology biotech. Kazia’s chief medical officer John Friend, M.D., has immediately assumed the role as CEO. Release
> The Daily Wire co-founder Ben Shapiro has joined Oramed Pharmaceuticals’ board. Shapiro beneficially owns more than 4% of the company’s outstanding stock, making him a significant shareholder. Release
> Resolution Therapeutics has tapped Novartis’ Clifford Brass, M.D., Ph.D., to serve as chief medical officer. Clifford had been with Big Pharma Novartis since 2011, most recently working as VP and head of clinical sciences for hepatology, gastroenterology and transplantation. Release
> Vera Therapeutics has tapped Kerry Cooper, M.D., to serve as SVP of medical affairs. Cooper joins Vera from ProKidney and has held leadership roles at AstraZeneca and Amgen in the past. Release
> Newron Pharmaceuticals is shaking up its senior management team with one departure and two promotions. At the end of June, longtime EVP of Business Development Marco Caremi will retire, while Director of Business Development Laura Faravelli will be promoted to VP of business development and VP of Finance Roberto Galli will become chief financial officer. Release
> Curve Therapeutics has circled up a new VP of drug discovery. Monika Ermann, Ph.D., is joining the company from Exscientia, where she was director of chemical biology. Release
> Amphista Therapeutics’ chief scientific officer Ian Churcher is taking on the new role of chief technology officer, while Louise Modis, Ph.D., is stepping into the CSO role. Modis joins from Mogrify and has experience across GSK, Boehringer Ingelheim and Millennium Pharmaceuticals. Release
> Anaphylaxis-focused Bryn Pharma has expanded with the addition of three new executives: Nurry Hong as chief strategy and business development officer, Steve Killmeyer as chief financial officer and Lisa Lucifero as VP and head of human resources. Most recently, Hong served as CEO of Pareto Bio, Killmeyer was head of finance and strategy for Nestle Health Science’s Aimmune Therapeutics and Lucifero was head of HR for DBV Technologies’ U.S. and Australian arms. Release
> Tris Pharma is welcoming Thomas Englese as chief commercial officer and Marc Lesnick, Ph.D., as chief development officer. Englese joins from Aziyo Biologics, where he was also CCO, while Lesnick joins from Park Therapeutics, where he was chief development officer and co-founder. Release
> Iulia Diaconu, Ph.D., has started as chief scientific officer at Unikum Therapeutics. The scientist has previously worked at ElevateBio and bluebird bio. Release
> Jason Slingsby, Ph.D., has left Oxford Biomedical after eight years, joining medical research charity LifeArc as chief business officer. Release
Incoming Cerevel Therapeutics CEO Ron Renaud will have the opportunity to flip over seven data cards in the next 12 to 18 months.
Four years after taking the helm of Cerevel Therapeutics, Tony Coles, M.D., is stepping down, handing the reins over to Ron Renaud as the neuroscience biotech waits on seven data readouts.
Bain Capital Partner Renaud has “great experience and a terrific track record,” Coles told Fierce Biotech, adding that Renaud will be able to “build on the foundation of the company and take it to the next level.”
Starting June 12, Renaud will become the neurological-disease-focused biotech’s new president, CEO and board member. Coles will return to his role of chair of the board, a position he held back in 2018.
Coles, who led Onyx Pharmaceuticals to its $10 billion takeover by Amgen in 2013, took on the CEO role of Pfizer spinout Cerevel to “build a business,” the leader said. Under his direction, Cerevel went public in 2020 and has raised more than $1.5 billion total since its 2018 launch, including an initial $350 million from Bain Capital.
Now, Coles hands the baton to longtime friend Renaud.
“I've known Tony for over 10 years—I've been a CEO for over 10 years,” Renaud said in an interview. “So, this is ... I think, a really nice transition point for me.”
Renaud helmed mRNA-based Translate Bio for seven years until late 2021, when the company was officially acquired by Sanofi for $3.2 billion. Before that, he served as president and CEO of Idenix Pharmaceuticals, which was acquired by Merck & Co. for $3.85 billion in 2014. The executive has also served as chair of several biotechs, such as Atara Biotherapeutics, Ikena Oncology and Axial Biotherapeutics, among others. Most recently, he served as a partner at Bain, the global private investment firm that backs Cerevel and other biotechs like Areteia Therapeutics and Emalex Biosciences—companies that landed the No. 2 and No. 6 spots on Fierce Biotech’s list of top money raisers for 2022, respectively.
“We were looking for someone who had strong operating experience as a previous CEO,” Coles explained about his successor. “In this case, we get two prior CEO stats, so we consider that a double bonus.”
The change-up comes at a “critical inflection point,” according to Coles. The biotech—which is focused on neurological diseases including Parkinson’s, epilepsy and schizophrenia—had a balance sheet of $863 million as of March 31, money anticipated to carry the company into 2025 and through seven data readouts.
Renaud said he couldn’t predict what his main priorities will be when he takes charge but that he’ll be laser-focused on executing the data readouts.
One of those readouts is for emraclidine, a muscarinic M4 selective positive allosteric modulator currently being evaluated in a phase 2 trial in patients with schizophrenia who experience psychosis. Safety data from a phase 1b study showed that the drug doesn’t raise blood pressure—a concern for patients who may require chronic dosing—and the company is now focused on an efficacy readout set for the first half of 2024. The biotech is hoping to position the therapy as a new standard of care that sheds debilitating side effects associated with blocking dopamine receptors.
Renaud said Cerevel isn’t just hoping for a commercial launch for emraclidine but planning on it. The biotech is also studying the asset among patients with Alzheimer’s disease psychosis in a phase 1 trial, an indication the drug snagged an FDA fast-track designation for. The pressure is on, as Cerevel faces stiff competition from Karuna Therapeutics, a biotech that is also going after psychosis tied to schizophrenia or Alzheimer’s with its asset KarXT.
Other expected readouts for Cerevel include a phase 2 data for darigabat in epilepsy; phase 3 results for D1/D5 partial agonist tavapadon for Parkinson’s; and a phase 2a study of a D1/D5 partial agonist CVL-871 for treating dementia-related apathy.
The opportunity to flip over seven cards in the next 12 to 18 months positions Cerevel nicely, Renaud said.
“He'll be able to turn those cards over as those trials read out and really lead the company in what will be an explosive phase of growth,” Coles added on.
When asked about future plans, Coles said his main focus is on Cerevel’s chair role but he’d “never say never” to other potential biotech opportunities. However, the leader said he has lots of passions that extend beyond the life sciences space, including his work as a board member and co-founder of the Black Economic Alliance, an organization that looks at solutions to address the wealth and income gaps for Black Americans.
“I have spent a lot of my time on social, social justice and economic equity issues for Black Americans,” Cole said. “I suspect I'll be spending a lot more time for those kinds of things.”
Cerevel Therapeutics said Wednesday that former Bain Capital partner Ron Renaud has been appointed to succeed Tony Coles as the company's next chief executive, starting June 12. Renaud will also take up the post as company president, while Coles will continue in his role as chairperson of the board of directors.According to Cerevel, Renaud brings more than 25 years of experience in the biotechnology industry, including "deep expertise" in executive leadership, finance and operations. The company noted that Renaud's expertise includes stints as CEO at Translate Bio, which he "led from an early-stage start-up to a public company with a leading mRNA technology platform," as well as at Idenix Pharmaceuticals, where he "established a promising portfolio of potential treatments for hepatitis C."In the four years since Cerevel spun out from Pfizer with a focus on neuroscience, "we have delivered positive data readouts that support [our] scientific thesis, built a world-class team, debuted as a public company, and raised more than $1.5 billion in capital," Coles stated. "With strong business fundamentals in place and a robust pipeline of important programmes advancing in the clinic, now is the right time for me to transition back to the role of chairperson," he added. Coles had led Cerevel since 2019.Earlier this year, the company disclosed a delay in clinical readouts for multiple neuroscience drug candidates, including darigabat, which is in Phase II for focal epilepsy, as well as for the late-stage candidate tavapadon in Parkinson's disease. On Wednesday, Cerevel said the readout for darigabat is now expected in mid-year 2024. As for tavapadon, the company reiterated that data from the Phase III TEMPO-3 trial are due in the first half of 2024, while readouts from two other late-stage studies – TEMPO-1 and TEMPO-2 – are expected in the second half of next year."I am thrilled to join Cerevel and lead this incredible organisation into an exciting future, starting with the seven expected data readouts coming in 2024," said Renaud, adding that the company "has an impressive track record of success, and I look forward to all that is to come."