Two months after inking a SPAC deal, Renovacor taps new CMO; CureVac reels in a new development chief from Merck KGaA
Marc Semigran
Marc Semigran was at sleepaway camp in Hopewell Junction, NY, when Neil Armstrong took the first steps on the moon. He packed into a social hall with a couple of hundred kids whose eyes were glued to one small, staticky, black-and-white…
Marc Semigran was at sleepaway camp in Hopewell Junction, NY, when Neil Armstrong took the first steps on the moon. He packed into a social hall with a couple of hundred kids whose eyes were glued to one small, staticky, black-and-white television as Armstrong descended the ladder.
It sparked an interest in physics for Semigran whose focus later turned to medicine because he wanted to help people. That, and “I’m probably too tall, I don’t think I would have made it as an astronaut,” he quipped.
He went on to Harvard Medical School, then an internship and residency at the renowned Massachusetts General Hospital. His cardiology work there eventually led to a gig as CMO of MyoKardia, where he stayed until the company was bought out by Bristol Myers Squibb for a whopping $13.1 billion last year. And now, he’s taking the same role at gene therapy-focused Renovacor, just as the company prepares to go public on the back of a SPAC.
“Something that really reassured me about my decision was that we will have the funds to be able to carry out the scientific mission,” he said. Upon closing its deal with the blank-check company Chardan Healthcare Acquisition 2 Corp, Renovacor is set to pocket gross proceeds of up to $116 million.
Semigran joined MyoKardia back in 2016, where he oversaw Phase I and II studies and the design of registrational studies, worked with regulators, and helped file the NDA for mavacamten — MyoKardia’s drug for obstructive cardiomyopathy. In 2019, Semigran was promoted to senior VP of medical sciences. The FDA set a decision date of Jan. 28, 2022, for mavacamten, the same year that Renovacor is hoping to get IND clearance for REN-001, its gene therapy for BAG3-associated dilated cardiomyopathy (DCM).
“It would be great,” he said, if one of his drugs gets approved in the same year that another enters the clinic.
“So many of our therapies for heart failure really address manifestations of heart failure, rather than the primary underlying problem,” Semigran said. “Differentiating by cause is really what we need to do with heart failure… Both REN-001 and mavacamten address very different segments of the heart failure population, and we need them both.”
BAG3 protein is expressed predominantly in the heart, where it plays a role in the maintenance of sarcomeres, normalization of protein quality control, inhibition of programmed cell death, and responsiveness to adrenergic signals. BAG3 DCM has an average onset at 38 years old, and a survival rate of less than 50% five years after discovery.
“Certainly, our first and primary target is to address the patients with the genetic mutations in BAG3. But as we learn more from treating these patients, there may be the possibility of expansion to other heart failure patients,” Semigran said, or even other organs. — Nicole DeFeudis
Klaus Edvardsen
CureVac, the runner up mRNA company making a new vaccine for Covid-19, has poached their new development chief from Merck KGaA.
The German biotech reported it recruited Merck KGaA’s Klaus Edvardsen for chief development officer. Edvardsen had been head of oncology for the German Merck, making him a good cultural fit with CureVac. He had earlier served a stint as head of oncology development at AstraZeneca and had worked at GSK and Genmab before that.
He has a tremendous background, having led both business development and clinical research on a global scale for several high-profile biopharmaceutical companies. His great breadth of knowledge and expertise in research and different therapeutic areas will serve CureVac well as it continues to evolve from a research-oriented biotechnology to a fully integrated biopharmaceutical company,” observed Jean Stéphenne, chairman of the supervisory board of CureVac. — John Carroll
Nurix Therapeutics is celebrating the addition of its newest board member, and it’s reeled in a high-profile biotech CEO.
Clay Siegall
Clay Siegall of Seagen is hopping onto the board, Nurix announced this week, joining the protein degradation player that’s secured partnerships with Gilead and Sanofi. The move comes as Nurix is expected to launch clinical studies for three product candidates sometime before the end of the year.
Siegall made his name by founding Seagen as Seattle Genetics way back in 1998, and has transformed it into one of the larger biotechs in the US. Under Siegall’s leadership, Seagen has shepherded three drugs past the finish line with the potential for a fourth in October.
It’s pinned blockbuster hopes on one of its drugs, the Nectin-4 targeting therapy Padcev, which saw sales more than double to $69.8 million in the first quarter in 2021 compared to 2020.
Siegall himself has made a pretty penny as the company’s chief executive, pulling in a $16.5 million pay package last year — a figure that approaches some of the biggest names in pharma. It’s also the largest package for any CEO in the state of Washington, according to an Associated Pressreport.
Nurix, meanwhile, is continuing to charge ahead with its pipeline. The programs expected to hit Phase I studies soon comprise a small molecule degrader of BTK called NX-5948, and with it, Nurix hopes to target autoimmune diseases. There are also two ligase inhibitors where Nurix is going after an immuno-oncology target and tumor infiltrating lymphocytes, respectively.
Their lead candidate is a dual degrader of both BTK and Aiolos, a protein target of IMiD drugs, known as NX-2127. It recently began its own clinical trial, the first Nurix has launched.
In addition to Nurix’s board, Siegall also serves on the boards of Ultragenyx and Washington Roundtable, a lobbyist group comprising several executives from the state. — Max Gelman
Ronald Martell
→ Private platform company Morphimmunehas selectedRonald Martell as the company’s new CEO and president. The new stint at the San Francisco-based company isn’t Martell’s first rodeo in the CEO chair. Martell was previously running gigs at NuvelationPharma, AchieveLife Sciences, Sevion and NeurogesX. Additionally, Martell was co-founder and executive chairman of Indapta and OrcaBio. Earlier in his career, Martell was with Genentech and ImClone Systems, where he was making deals with Bristol Myers Squibb and Merck KGaA.
→ Stefan König, the former Takeda VP and global franchise head, inflammatory bowel disease, has hopped into the CEO seat at George Medicines. In his most recent role at Takeda, König was responsible for Entyvio (vedolizumab). König’s earlier roles at Takeda included regional managing director for a cluster of countries in Central and Eastern Europe. In addition, König spent 10 years in Mexico and Latin America working in business and corporate development and marketing for Merck and Novartis.
→Decibel Therapeutics has added a new chairman as it continues a now-more-than-yearlong pivot to gene therapy and regeneration.
William Carson
The Cambridge biotech named William Carson, former CEO of Otsuka Pharmaceuticals, as chair. Carson will serve as a delayed replacement for former Biogen CEO George Scangos, a longtime colleague of Steve Holtzman, Decibel’s former chief executive. Decibel quietly disclosed in their S-1 this January that Scangos had resigned from the board in June 2020, five months after Holtzman retired and the company shifted focus.
Otsuka, a psychiatrist, served on the board at Prevail before its buyout by Eli Lilly and is now on the boards at Sana, Annexon, Otsuka and Excision Biotherapeutics. His appointment comes amid a series of changes Decibel has made to burnish its credentials, most recently expanding its scientific advisory board with a clutch of well-regarded gene therapy and hearing experts.
→ Patrick Flaniganis hopping aboardNancy Thornberry’s gut-brain axis biotech Kallyope as CFO. Flanigan joins the crew from Ichnos Sciences, where he also served as CFO. Flanigan jumpstarted his career at Genzyme, where he served as VP of investor relations before hopping over to Celgene as SVP.
→ Nanobiotixhas ushered in a new CFO two days prior to presenting some positive early data at #ASCO21 for their tumor-shrinking tech. Bart Van Rhijn, who joins the company after a stint as CFO of Servier Pharmaceuticals, will be succeeding outgoing CFO Philippe Mauberna. Prior to his role at Servier, Van Rhijn was with PricewaterhouseCoopers, Philips and Galderma. Additionally, Van Rhijn has been appointed to the company’s executive board.
Molly Gibson
→ AI biotech Generate Biomedicines has reeled in Mike Nohaile as CSO. Nohaile hails from Flagship Pioneering, where he served as operating partner. Prior to Flagship, Nohaile was with Amgen, where he served as SVP of strategy, commercialization, and innovation.
In addition to Nohaile’s appointment, Molly Gibson — who was honored in our 2020 20 under 40 special — will be expanding her role at Generate, tacking on new responsibilities as chief strategy and innovation officer. Prior to Generate, Gibson, who is a principal of Flagship Pioneering, led computational biology at Kaleido Biosciences.
→ ValenzaBio — whose oncology island of misfit toys snared $70 million in April — has waved inGregoryKeenan as CMO. Keenan joins the Bethesda, MD-based team from Avrobio, where he served as SVP, global head of medical and drug safety. Prior to that, he served in stints at AstraZeneca, Medimmune, Human Genome Sciences and Centocor OrthoBiotech.
In addition to Keenan’s appointment, the crew has also welcomed CEO of RibometrixMike Solomon into the fold as part of its board of directors. Solomon was a former venture partner of SV Health Investors; COO of Decibel Therapeutics, and entrepreneur in residence at Third Rock Ventures among other stints.
Michael MacLean
→What better way to prep for an IPO than adding a well-regarded CFO to your board? Verve Therapeutics, Sekar Kathiresan’s cardiovascular gene-editing startup, announced they had named Michael MacLean, former CFO of Avidity Biosciences, to its board. In addition to Avidity, MacLean has also worked as CFO of PureTech and Ionis spinout Akcea. Verve has penciled in $100 million for their public offering, although they are widely expected to raise significantly more.
→ David Hung has recruited a supply chain expert to ensure that the cancer drugs he’s developing at Nuvation Bio will be ready whenever he needs them. As chief technical operations officer, David Hanley is tasked with overseeing everything from product development to manufacturing, while also working on commercial planning with other teams — in short, dedicated to product readiness at all stages, whether it be preclinical or marketing. He joins from Radius Health just as Nuvation is pushing a Phase I/II study of the lead candidate, which targets CDK 2/4/6, and lining up five others for the clinic.
Wayne Godfrey
→ While aiming for an IPO after coming off the presses with a $1 billion deal with Merck, Janux Therapeuticshas selectedWayne Godfrey as CMO. Godfrey comes from IGMBiosciences, where he served as VP of clinical development. Before that, he was with Kite Pharma, Etubics, Gilead and Bavarian-Nordic.
→ Beleaguered biotech Onconova Therapeutics — which axed its high-risk MDS program after another PhIII flop — has namedMark Gelder as CMO. Gelder hops aboard from ElevarTherapeutics, where he served in the same role. Prior to Elevar, Gelder was working with Pierian Biosciences, Accelovance, Heron Therapeutics, Pfizer, Wyeth and Bayer.
→ Launched by Frazier Healthcare Partners last May with a $15 million Series A, San Diego-based oncology drug developer Lengo Therapeuticshas madeDiana Hausman CMO. Hausman comes aboard after a stint as CMO for Zymeworks. Prior to that, she served at ZymoGenetics, Berlex and Immunex. Hausman’s appointment comes three weeks after Lengo snagged the CEO of VelosBioDave Johnson as chairman of the board.
Diana Hausman
→ Evelo Bioscienceshas appointedMark Plinio as CCO. Plinio comes to Evelo from Ironwood Pharmaceuticals, where he was CCO and SVP, marketing and sales. Prior to his gig at Ironwood, Plinio spent nearly two decades at Novartis in a variety of roles including head of dermatology and rheumatology marketing for Cosentyx.
→ JSR Life Sciences company Selexishas namedRoland Hoffmann-Hecht as CBO. Hoffmann-Hecht hails from PolpharmaBiologics, where he was head of business development, CDMO Europe. Prior to that, he held roles at Halix, BIOMEVAGmbH, CMCBiologics and Rentschler Biotechnologie GmbH.
Wan-Jen Hong
→ Blood cancer player Imago Bioscienceshas appointedWan-Jen Hong as CMO. Hong hails from Genentech, where she served as group medical director. Hong previously was a clinical instructor in hematology at Stanford University School of Medicine and is the current adjunct clinical faculty member in its division of hematology.
→ After emerging from stealth mode last June with $118 million in its pocket from Redmile Group and over 10 other investors, Shattuck Labshas baggedAbhinav Shukla as chief technical officer. Shukla joins the Austin, TX-based team from Redpin Therapeutics, having served as chief technical operations officer. Prior to that, Shukla was with CRISPRTherapeutics, Shire, Bristol Myers, Amgen and KBIBiopharma.
→ A couple of months after emerging from stealth mode with a $100 million Series B round and a mission to outsmart cancer resistance, Theseus Pharmaceuticals has tappedBrad Dahms as its new CFO. The former investment banker is coming from Selecta Biosciences, where he recently led a $730 million agreement to license the company’s chronic refractory gout treatment to Sobi. Before that, Dahms was a senior VP in the healthcare group at Cantor Fitzgerald & Co., and held roles at RBC Capital Markets and JP Morgan. Theseus, backed by OrbiMed, says it will use the Series B to advance a suite of “pan-variant” TKIs, including a lead compound targeting KIT-mutant gastrointestinal stromal tumors.
John Maslowski
→ Forge Biologics has reeled inJohn Maslowski into the new role of CCO. Maslowski jumps aboard from Castle Creek Biosciences, where he was president and CEO. He served in the same role at Fibrocell Science and had gigs at Wyeth, Merck and Teva. Maslowski was also the former chairman of the board of directors at Falcon Therapeutics.
→ Ovid Therapeuticsis expanding CBO’s JeffreyRona’s responsibilities to include the role of CFO. Rona joined the company in October 2020. Prior to Ovid, Rona was heading operations at Danforth Advisors as Western region managing director. Before that, he was running gigs as an exec at GlobeImmune, AlgoRx Pharmaceuticals and Great Basin Scientific.
Jeff Rona
→ AI-based diagnostic software in pathology company Paigehas appointed co-founder David Klimstra as CMO. Klimstra is currently the chair of the department of pathology at Memorial Sloan Kettering Cancer Center.
→ NEXGEL, a provider of hydrogels for healthcare and consumer applications, has brought inAdamDrapczuk as CFO. Prior to his new role at NEXGEL, Drapczuk was financial controller for R-Pharm US. Drapczuk has also had stints at Inpellis, Tris Pharma and West-Ward Pharmaceuticals.
→ Merck KGaA has welcomed a fresh slate of faces with the appointments of Amy Mahery as SVP, head of the neurology and immunology global business franchise; Jan Klatt as SVP, head of the development unit neurology & immunology; and Amy Kao as head of translational innovation platform immunology.
Mahery preciously served on the global market access team at Merck KGaA and serves as the healthcare representative on the Merck diversity council. Meanwhile, Klatt comes to the team from Novartis, where he most recently served as global program head, heart failure. Finally, Kao comes aboard from Biogen, where she worked in early clinical development in immunology.
→ Irish drug developer Avadel Pharmaceuticals — which saw its stock shoot up nearly 33% on narcolepsy data last April — has made a slew of new hires with the appointments of Jeff Cruikshank as VP, sales; Denise Strauss as VP, marketing and new product strategy and Angela Woods as VP, people and culture.
Denise Strauss
Cruikshank comes to the company with experience from Ironwood Pharmaceuticals, Novartis and Janssen Pharmaceuticals under his belt. Meanwhile, Strauss brings in her own expertise from her times at Genfit, Pfizer, Schering-Plough and Boehringer Ingelheim. Last but not least, Woods formerly served as VP, human resources at Mallinckrodt.
→ Athira Pharma, going after one of pharma’s trickiest fields in Alzheimer’s disease, has a new top lawyer. The Seattle-based biotech has tappedMark Worthington as their general counsel, where he comes after a 24-year stint at Summit Law Group. Athira went public in a $200 million-plus IPO in September 2020, and CEO Leen Kawas said in a statement that Worthington will be involved in “business growth and strategic plans.”
→ Immunic — whose lead drug failed to impress in 2 separate trials — has appointedInderpal Singh as general counsel. Singh joins the company from Sandoz International GmbH, where he was global legal head of biopharma. Prior to Sandoz, Singh was with Merck KGaA, Biogen Idec, Pfizer Deutschland GmbH and Pfizer.
→ Healthcare investor Gilde Healthcarehas snaggedJoep Muijrers to the investment team of its Venture & Growth capital fund. Muijrers will be responsible for Gilde’s investments in publicly-traded companies focused on therapeutics, healthtech and medical devices in Europe and the US. Muijrers formerly served as CFO and chief of portfolio strategy at PureTech Health.
→ Medical device Co Avisa Diagnosticshas addedBarbara Bunger to its executive team in the newly created position of VP, clinical development. Prior to her new role, Bunger served in roles at Clinical Development and Regulatory Services, Beckton Dickinson and Medtronic Spine & Biologics among others.
Micki Klearman
→ San Francisco’s Kezar Life Sciences — which bagged an $86.3 IPO back in 2018 — has enlistedMicki Klearman to its board of directors. Klearman brings to the board her experience from her time at Genentech/Roche, where she served as group medical director in immunology.
→ Melbourne-based Optheais bringing inJulia Haller and Judith Robertson as independent non-executive directors to its board of directors. Haller serves as professor and chair of the department of ophthalmology at Sidney Kimmel Medical College at Thomas Jefferson University. She also sits on the board of Bristol Myers and is president of the John Hopkins Medical and Surgical Association. Meanwhile, Robertson most recently served as CCO of Eleusis and was the former CCO of Aerie Pharmaceuticals. Before Arie, Robertson was serving at J&J, Janssen, BMS and Novartis.
Liz Cermak
→ NeuranaPharmaceuticals — focused on the treatment of neuromuscular conditions — has brought inGeorgia Erbez and J&J vet Elizabeth (Liz) Cermak to its board of directors. Erbez is the current CFO of Harpoon Therapeutics and formerly headed leadership roles at Zosana Pharma, AsteriasBiotherapeutics and RaptorPharmaceuticals. On the other hand, Cermak currently sits on the boards of Moleculin Biotech, Que Oncology and Clarus Therapeutics. Cermak’s previous experience includes roles at SteadyMed Therapeutics and POZEN.
→ AbbVie-partnered I-Mab has tapped two experts in China’s regulatory landscape to its board of directors. Ruyi He, now CSO at RemeGen, used to be the chief scientist at the National Medical Products Administration’s Center for Drug Evaluation, while Rong Shao is a professor drug administration policies and regulations, China Pharmaceutical University.
Ruyi He
→ Menlo Park, CA-based 180 Life Scienceshas welcomedRussell Ray and Teresa DeLuca to its board of directors. This is Ray’s second board seat, he also sits on the board of Merrimack Pharmaceuticals. Ray formerly served as managing director and co-head of global health care at Credit Suisse First Boston Corporation. Meanwhile, DeLuca comes aboard with experience from GSK, Medco, Walgreens, Humana and Magellan.
→ Biocom California, the association representing the California life science industry, has recruitedJuli Moran to its board of governors and Paul Mola to its board of directors. Moran is managing partner and managing director of Deloitte Consulting, while Mola is president, CEO and founder of Roswell Biotechnologies.
Chronic stress and inflammation linked to societal and environmental impacts in new study
From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors…
From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors can cause chronic inflammation in our bodies. Chronic inflammation is linked to serious conditions such as cardiovascular disease and cancer – and may also affect our thinking and behavior.
Credit: Image: Vodovotz et al/Frontiers
From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors can cause chronic inflammation in our bodies. Chronic inflammation is linked to serious conditions such as cardiovascular disease and cancer – and may also affect our thinking and behavior.
A new hypothesis published in Frontiers in Science suggests the negative impacts may extend far further.
“We propose that stress, inflammation, and consequently impaired cognition in individuals can scale up to communities and populations,” explained lead author Prof Yoram Vodovotz of the University of Pittsburgh, USA.
“This could affect the decision-making and behavior of entire societies, impair our cognitive ability to address complex issues like climate change, social unrest, and infectious disease – and ultimately lead to a self-sustaining cycle of societal dysfunction and environmental degradation,” he added.
Bodily inflammation ‘mapped’ in the brain
One central premise to the hypothesis is an association between chronic inflammation and cognitive dysfunction.
“The cause of this well-known phenomenon is not currently known,” said Vodovotz. “We propose a mechanism, which we call the ‘central inflammation map’.”
The authors’ novel idea is that the brain creates its own copy of bodily inflammation. Normally, this inflammation map allows the brain to manage the inflammatory response and promote healing.
When inflammation is high or chronic, however, the response goes awry and can damage healthy tissues and organs. The authors suggest the inflammation map could similarly harm the brain and impair cognition, emotion, and behavior.
Accelerated spread of stress and inflammation online
A second premise is the spread of chronic inflammation from individuals to populations.
“While inflammation is not contagious per se, it could still spread via the transmission of stress among people,” explained Vodovotz.
The authors further suggest that stress is being transmitted faster than ever before, through social media and other digital communications.
“People are constantly bombarded with high levels of distressing information, be it the news, negative online comments, or a feeling of inadequacy when viewing social media feeds,” said Vodovotz. “We hypothesize that this new dimension of human experience, from which it is difficult to escape, is driving stress, chronic inflammation, and cognitive impairment across global societies.”
Inflammation as a driver of social and planetary disruption
These ideas shift our view of inflammation as a biological process restricted to an individual. Instead, the authors see it as a multiscale process linking molecular, cellular, and physiological interactions in each of us to altered decision-making and behavior in populations – and ultimately to large-scale societal and environmental impacts.
“Stress-impaired judgment could explain the chaotic and counter-intuitive responses of large parts of the global population to stressful events such as climate change and the Covid-19 pandemic,” explained Vodovotz.
“An inability to address these and other stressors may propagate a self-fulfilling sense of pervasive danger, causing further stress, inflammation, and impaired cognition in a runaway, positive feedback loop,” he added.
The fact that current levels of global stress have not led to widespread societal disorder could indicate an equally strong stabilizing effect from “controllers” such as trust in laws, science, and multinational organizations like the United Nations.
“However, societal norms and institutions are increasingly being questioned, at times rightly so as relics of a foregone era,” said Prof Paul Verschure of Radboud University, the Netherlands, and a co-author of the article. “The challenge today is how we can ward off a new adversarial era of instability due to global stress caused by a multi-scale combination of geopolitical fragmentation, conflicts, and ecological collapse amplified by existential angst, cognitive overload, and runaway disinformation.”
Reducing social media exposure as part of the solution
The authors developed a mathematical model to test their ideas and explore ways to reduce stress and build resilience.
“Preliminary results highlight the need for interventions at multiple levels and scales,” commented co-author Prof Julia Arciero of Indiana University, USA.
“While anti-inflammatory drugs are sometimes used to treat medical conditions associated with inflammation, we do not believe these are the whole answer for individuals,” said Dr David Katz, co-author and a specialist in preventive and lifestyle medicine based in the US. “Lifestyle changes such as healthy nutrition, exercise, and reducing exposure to stressful online content could also be important.”
“The dawning new era of precision and personalized therapeutics could also offer enormous potential,” he added.
At the societal level, the authors suggest creating calm public spaces and providing education on the norms and institutions that keep our societies stable and functioning.
“While our ‘inflammation map’ hypothesis and corresponding mathematical model are a start, a coordinated and interdisciplinary research effort is needed to define interventions that would improve the lives of individuals and the resilience of communities to stress. We hope our article stimulates scientists around the world to take up this challenge,” Vodovotz concluded.
The article is part of the Frontiers in Science multimedia article hub ‘A multiscale map of inflammatory stress’. The hub features a video, an explainer, a version of the article written for kids, and an editorial, viewpoints, and policy outlook from other eminent experts: Prof David Almeida (Penn State University, USA), Prof Pietro Ghezzi (University of Urbino Carlo Bo, Italy), and Dr Ioannis P Androulakis (Rutgers, The State University of New Jersey, USA).
Journal
Frontiers in Science
DOI
10.3389/1239462
Method of Research
Computational simulation/modeling
Subject of Research
Not applicable
Article Title
A multiscale inflammatory map: linking individual stress to societal dysfunction
Article Publication Date
12-Mar-2024
COI Statement
YV is a cofounder of, and stakeholder in, Immunetrics, Inc. and a consultant to Anuna AI. PFMJV is the founder of, and stakeholder in, Eodyne Systems s.l. and Sapiens5 Holding BV. DLK was employed by Tangelo – Intend, Inc. Neither these companies nor the funders mentioned above were involved in the study design, data collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The companies mentioned above also did not provide funding for the study. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors YV and PV declared that they are editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Acadia’s Nuplazid fails PhIII study due to higher-than-expected placebo effect
After years of trying to expand the market territory for Nuplazid, Acadia Pharmaceuticals might have hit a dead end, with a Phase III fail in schizophrenia…
After years of trying to expand the market territory for Nuplazid, Acadia Pharmaceuticals might have hit a dead end, with a Phase III fail in schizophrenia due to the placebo arm performing better than expected.
Steve Davis
“We will continue to analyze these data with our scientific advisors, but we do not intend to conduct any further clinical trials with pimavanserin,” CEO Steve Davis said in a Monday press release. Acadia’s stock $ACAD dropped by 17.41% before the market opened Tuesday.
Pimavanserin, a serotonin inverse agonist and also a 5-HT2A receptor antagonist, is already in the market with the brand name Nuplazid for Parkinson’s disease psychosis. Efforts to expand into other indications such as Alzheimer’s-related psychosis and major depression have been unsuccessful, and previous trials in schizophrenia have yielded mixed data at best. Its February presentation does not list other pimavanserin studies in progress.
The Phase III ADVANCE-2 trial investigated 34 mg pimavanserin versus placebo in 454 patients who have negative symptoms of schizophrenia. The study used the negative symptom assessment-16 (NSA-16) total score as a primary endpoint and followed participants up to week 26. Study participants have control of positive symptoms due to antipsychotic therapies.
The company said that the change from baseline in this measure for the treatment arm was similar between the Phase II ADVANCE-1 study and ADVANCE-2 at -11.6 and -11.8, respectively. However, the placebo was higher in ADVANCE-2 at -11.1, when this was -8.5 in ADVANCE-1. The p-value in ADVANCE-2 was 0.4825.
In July last year, another Phase III schizophrenia trial — by Sumitomo and Otsuka — also reported negative results due to what the company noted as Covid-19 induced placebo effect.
According to Mizuho Securities analysts, ADVANCE-2 data were disappointing considering the company applied what it learned from ADVANCE-1, such as recruiting patients outside the US to alleviate a high placebo effect. The Phase III recruited participants in Argentina and Europe.
Analysts at Cowen added that the placebo effect has been a “notorious headwind” in US-based trials, which appears to “now extend” to ex-US studies. But they also noted ADVANCE-1 reported a “modest effect” from the drug anyway.
Nonetheless, pimavanserin’s safety profile in the late-stage study “was consistent with previous clinical trials,” with the drug having an adverse event rate of 30.4% versus 40.3% with placebo, the company said. Back in 2018, even with the FDA approval for Parkinson’s psychosis, there was an intense spotlight on Nuplazid’s safety profile.
Acadia previously aimed to get Nuplazid approved for Alzheimer’s-related psychosis but had many hurdles. The drug faced an adcomm in June 2022 that voted 9-3 noting that the drug is unlikely to be effective in this setting, culminating in a CRL a few months later.
As for the company’s next R&D milestones, Mizuho analysts said it won’t be anytime soon: There is the Phase III study for ACP-101 in Prader-Willi syndrome with data expected late next year and a Phase II trial for ACP-204 in Alzheimer’s disease psychosis with results anticipated in 2026.
Acadia collected $549.2 million in full-year 2023 revenues for Nuplazid, with $143.9 million in the fourth quarter.
"Beware the Ides of March,” Shakespeare quotes the soothsayer’s warning Julius Caesar about what turned out to be an impending assassination on March 15. The death of American liberty happened around the same time four years ago, when the orders went out from all levels of government to close all indoor and outdoor venues where people gather.
It was not quite a law and it was never voted on by anyone. Seemingly out of nowhere, people who the public had largely ignored, the public health bureaucrats, all united to tell the executives in charge – mayors, governors, and the president – that the only way to deal with a respiratory virus was to scrap freedom and the Bill of Rights.
And they did, not only in the US but all over the world.
The forced closures in the US began on March 6 when the mayor of Austin, Texas, announced the shutdown of the technology and arts festival South by Southwest. Hundreds of thousands of contracts, of attendees and vendors, were instantly scrapped. The mayor said he was acting on the advice of his health experts and they in turn pointed to the CDC, which in turn pointed to the World Health Organization, which in turn pointed to member states and so on.
There was no record of Covid in Austin, Texas, that day but they were sure they were doing their part to stop the spread. It was the first deployment of the “Zero Covid” strategy that became, for a time, official US policy, just as in China.
It was never clear precisely who to blame or who would take responsibility, legal or otherwise.
This Friday evening press conference in Austin was just the beginning. By the next Thursday evening, the lockdown mania reached a full crescendo. Donald Trump went on nationwide television to announce that everything was under control but that he was stopping all travel in and out of US borders, from Europe, the UK, Australia, and New Zealand. American citizens would need to return by Monday or be stuck.
Americans abroad panicked while spending on tickets home and crowded into international airports with waits up to 8 hours standing shoulder to shoulder. It was the first clear sign: there would be no consistency in the deployment of these edicts.
There is no historical record of any American president ever issuing global travel restrictions like this without a declaration of war. Until then, and since the age of travel began, every American had taken it for granted that he could buy a ticket and board a plane. That was no longer possible. Very quickly it became even difficult to travel state to state, as most states eventually implemented a two-week quarantine rule.
The next day, Friday March 13, Broadway closed and New York City began to empty out as any residents who could went to summer homes or out of state.
On that day, the Trump administration declared the national emergency by invoking the Stafford Act which triggers new powers and resources to the Federal Emergency Management Administration.
In addition, the Department of Health and Human Services issued a classified document, only to be released to the public months later. The document initiated the lockdowns. It still does not exist on any government website.
The White House Coronavirus Response Task Force, led by the Vice President, will coordinate a whole-of-government approach, including governors, state and local officials, and members of Congress, to develop the best options for the safety, well-being, and health of the American people. HHS is the LFA [Lead Federal Agency] for coordinating the federal response to COVID-19.
Closures were guaranteed:
Recommend significantly limiting public gatherings and cancellation of almost all sporting events, performances, and public and private meetings that cannot be convened by phone. Consider school closures. Issue widespread ‘stay at home’ directives for public and private organizations, with nearly 100% telework for some, although critical public services and infrastructure may need to retain skeleton crews. Law enforcement could shift to focus more on crime prevention, as routine monitoring of storefronts could be important.
In this vision of turnkey totalitarian control of society, the vaccine was pre-approved: “Partner with pharmaceutical industry to produce anti-virals and vaccine.”
The National Security Council was put in charge of policy making. The CDC was just the marketing operation. That’s why it felt like martial law. Without using those words, that’s what was being declared. It even urged information management, with censorship strongly implied.
The timing here is fascinating. This document came out on a Friday. But according to every autobiographical account – from Mike Pence and Scott Gottlieb to Deborah Birx and Jared Kushner – the gathered team did not meet with Trump himself until the weekend of the 14th and 15th, Saturday and Sunday.
According to their account, this was his first real encounter with the urge that he lock down the whole country. He reluctantly agreed to 15 days to flatten the curve. He announced this on Monday the 16th with the famous line: “All public and private venues where people gather should be closed.”
This makes no sense. The decision had already been made and all enabling documents were already in circulation.
There are only two possibilities.
One: the Department of Homeland Security issued this March 13 HHS document without Trump’s knowledge or authority. That seems unlikely.
Two: Kushner, Birx, Pence, and Gottlieb are lying. They decided on a story and they are sticking to it.
Trump himself has never explained the timeline or precisely when he decided to greenlight the lockdowns. To this day, he avoids the issue beyond his constant claim that he doesn’t get enough credit for his handling of the pandemic.
With Nixon, the famous question was always what did he know and when did he know it? When it comes to Trump and insofar as concerns Covid lockdowns – unlike the fake allegations of collusion with Russia – we have no investigations. To this day, no one in the corporate media seems even slightly interested in why, how, or when human rights got abolished by bureaucratic edict.
As part of the lockdowns, the Cybersecurity and Infrastructure Security Agency, which was and is part of the Department of Homeland Security, as set up in 2018, broke the entire American labor force into essential and nonessential.
They also set up and enforced censorship protocols, which is why it seemed like so few objected. In addition, CISA was tasked with overseeing mail-in ballots.
Only 8 days into the 15, Trump announced that he wanted to open the country by Easter, which was on April 12. His announcement on March 24 was treated as outrageous and irresponsible by the national press but keep in mind: Easter would already take us beyond the initial two-week lockdown. What seemed to be an opening was an extension of closing.
This announcement by Trump encouraged Birx and Fauci to ask for an additional 30 days of lockdown, which Trump granted. Even on April 23, Trump told Georgia and Florida, which had made noises about reopening, that “It’s too soon.” He publicly fought with the governor of Georgia, who was first to open his state.
Before the 15 days was over, Congress passed and the president signed the 880-page CARES Act, which authorized the distribution of $2 trillion to states, businesses, and individuals, thus guaranteeing that lockdowns would continue for the duration.
There was never a stated exit plan beyond Birx’s public statements that she wanted zero cases of Covid in the country. That was never going to happen. It is very likely that the virus had already been circulating in the US and Canada from October 2019. A famous seroprevalence study by Jay Bhattacharya came out in May 2020 discerning that infections and immunity were already widespread in the California county they examined.
What that implied was two crucial points: there was zero hope for the Zero Covid mission and this pandemic would end as they all did, through endemicity via exposure, not from a vaccine as such. That was certainly not the message that was being broadcast from Washington. The growing sense at the time was that we all had to sit tight and just wait for the inoculation on which pharmaceutical companies were working.
By summer 2020, you recall what happened. A restless generation of kids fed up with this stay-at-home nonsense seized on the opportunity to protest racial injustice in the killing of George Floyd. Public health officials approved of these gatherings – unlike protests against lockdowns – on grounds that racism was a virus even more serious than Covid. Some of these protests got out of hand and became violent and destructive.
Meanwhile, substance abuse rage – the liquor and weed stores never closed – and immune systems were being degraded by lack of normal exposure, exactly as the Bakersfield doctors had predicted. Millions of small businesses had closed. The learning losses from school closures were mounting, as it turned out that Zoom school was near worthless.
It was about this time that Trump seemed to figure out – thanks to the wise council of Dr. Scott Atlas – that he had been played and started urging states to reopen. But it was strange: he seemed to be less in the position of being a president in charge and more of a public pundit, Tweeting out his wishes until his account was banned. He was unable to put the worms back in the can that he had approved opening.
By that time, and by all accounts, Trump was convinced that the whole effort was a mistake, that he had been trolled into wrecking the country he promised to make great. It was too late. Mail-in ballots had been widely approved, the country was in shambles, the media and public health bureaucrats were ruling the airwaves, and his final months of the campaign failed even to come to grips with the reality on the ground.
At the time, many people had predicted that once Biden took office and the vaccine was released, Covid would be declared to have been beaten. But that didn’t happen and mainly for one reason: resistance to the vaccine was more intense than anyone had predicted. The Biden administration attempted to impose mandates on the entire US workforce. Thanks to a Supreme Court ruling, that effort was thwarted but not before HR departments around the country had already implemented them.
As the months rolled on – and four major cities closed all public accommodations to the unvaccinated, who were being demonized for prolonging the pandemic – it became clear that the vaccine could not and would not stop infection or transmission, which means that this shot could not be classified as a public health benefit. Even as a private benefit, the evidence was mixed. Any protection it provided was short-lived and reports of vaccine injury began to mount. Even now, we cannot gain full clarity on the scale of the problem because essential data and documentation remains classified.
After four years, we find ourselves in a strange position. We still do not know precisely what unfolded in mid-March 2020: who made what decisions, when, and why. There has been no serious attempt at any high level to provide a clear accounting much less assign blame.
Not even Tucker Carlson, who reportedly played a crucial role in getting Trump to panic over the virus, will tell us the source of his own information or what his source told him. There have been a series of valuable hearings in the House and Senate but they have received little to no press attention, and none have focus on the lockdown orders themselves.
The prevailing attitude in public life is just to forget the whole thing. And yet we live now in a country very different from the one we inhabited five years ago. Our media is captured. Social media is widely censored in violation of the First Amendment, a problem being taken up by the Supreme Court this month with no certainty of the outcome. The administrative state that seized control has not given up power. Crime has been normalized. Art and music institutions are on the rocks. Public trust in all official institutions is at rock bottom. We don’t even know if we can trust the elections anymore.
In the early days of lockdown, Henry Kissinger warned that if the mitigation plan does not go well, the world will find itself set “on fire.” He died in 2023. Meanwhile, the world is indeed on fire. The essential struggle in every country on earth today concerns the battle between the authority and power of permanent administration apparatus of the state – the very one that took total control in lockdowns – and the enlightenment ideal of a government that is responsible to the will of the people and the moral demand for freedom and rights.
How this struggle turns out is the essential story of our times.
CODA: I’m embedding a copy of PanCAP Adapted, as annotated by Debbie Lerman. You might need to download the whole thing to see the annotations. If you can help with research, please do.
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