Axsome update post-Q3 report

 Business Update

Axsome is committed to developing products that meaningfully improve the lives of patients. The Company is developing a portfolio of differentiated, patent-protected, CNS product candidates with four in active clinical development.

AXS-05

AXS-05 (dextromethorphan-bupropion) is Axsome’s novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for the following indications: major depressive disorder (MDD), Alzheimer’s disease (AD) agitation, and smoking cessation. AXS-05 has been granted U.S. Food and Drug Administration (FDA) Breakthrough Therapy designations for MDD and for AD agitation.

• Depression: Axsome’s New Drug Application (NDA) for AXS-05 for the treatment of MDD was granted Priority Review and is currently under review by the FDA. On August 20, 2021, the FDA informed the Company in a teleconference that its review of the NDA would not be completed by the Prescription Drug User Fee Act (PDUFA) target action date of August 22, 2021. The Company was recently informed of two deficiencies related to analytical methods in the Chemistry, Manufacturing, and Controls (CMC) section of the NDA, which must be addressed prior to the FDA taking action on the NDA. The Company believes these deficiencies are addressable and is confirming the details of the request with the FDA.

• Alzheimer’s Disease Agitation: Axsome is conducting the ACCORD study, a Phase 3, double-blind, placebo-controlled, multicenter, randomized withdrawal trial to evaluate the efficacy and safety of AXS-05 in the treatment of Alzheimer’s disease (AD) agitation. Based on current enrollment trends, Axsome now anticipates completion of the trial in the first half of 2023.

• Smoking Cessation: Axsome has received from the FDA positive Pre-Investigational New Drug Application (Pre-IND) meeting written guidance from the FDA on a proposed clinical developmental plan for dextromethorphan-bupropion as an aid to smoking cessation. Based on this feedback, Axsome plans to proceed to a pivotal Phase 2/3 trial in this indication. The Company intends to provide information on the timing of initiation of this study in 2022.
  

AXS-07

AXS-07 (MoSEIC™ meloxicam-rizatriptan) is Axsome’s novel, oral, rapidly absorbed, multi-mechanistic, investigational medicine for the acute treatment of migraine.

• Migraine: Axsome’s NDA for AXS-07 for the acute treatment of migraine was accepted for review by the FDA. The FDA has set a PDUFA target action date for the NDA of April 30, 2022. The FDA notified the Company that, due to COVID-19 pandemic-related travel restrictions, they may be unable to complete a required inspection of a contract manufacturing facility, located in the United States, prior to the PDUFA date, and that they will continue to monitor the public health situation as well as travel restrictions.
  

AXS-12

AXS-12 (reboxetine) is Axsome’s novel, oral, potent, and highly selective norepinephrine reuptake inhibitor for the treatment of narcolepsy. AXS-12 has been granted FDA Orphan Drug designation for the treatment of narcolepsy.

• Narcolepsy: In September 2021, Axsome initiated the SYMPHONY study, a Phase 3 randomized, multicenter, double-blind, placebo-controlled, parallel-group trial of AXS-12 in the treatment of narcolepsy. Enrollment in the trial is progressing and topline results are anticipated in the first half of 2023.
  

AXS-14

AXS-14 (esreboxetine) is Axsome’s novel, oral, potent, and highly selective norepinephrine reuptake inhibitor for the management of fibromyalgia. Esreboxetine, the SS-enantiomer of reboxetine, is more potent and selective than racemic reboxetine.

• Fibromyalgia: Manufacturing and other activities related to the planned submission of an NDA for AXS-14 for the management of fibromyalgia are ongoing. Based on the status of these activities, the Company now expects to submit the NDA in 2023. AXS-14 has previously met the primary endpoints and demonstrated positive and statistically significant results in a Phase 3 and in a Phase 2 trial for the management of fibromyalgia.
  

Commercial and Launch-Readiness Activities

Axsome is finalizing preparations for a commercial launch of AXS-05 for the treatment of MDD, if approved, and continues with preparations for a launch of AXS-07 for the acute treatment of migraine, if approved:

• Axsome’s Digital Centric Commercialization™ (DCC) platform design and technology implementation are complete. To ensure a smooth execution at launch, testing of the integrated technology and tools is on-going.

• With the field leadership team on board, field force activities have been focused on recruitment. At this time, the field force team build is essentially complete with all signed offers contingent upon approval. The Company anticipates having all field representatives on board by launch.

• The market access team continues to engage in permitted ongoing discussion with payers, ensuring awareness of Axsome and of the product profiles of both AXS-05 and AXS-07.

• All marketing materials and patient support services for AXS-05 are ready for execution in anticipation of a potential approval.

• Commercial activities related to AXS-07 are on-going and progressing accordingly.

https://finance.yahoo.com/news/axsome-therapeutics-reports-third-quarter-120000880.html

Alnylam Initiates Phase 2 Study of Zilebesiran in Hypertension

 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced initiation of KARDIA-2, a global Phase 2 study to evaluate the efficacy and safety of zilebesiran (formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. KARDIA-2 will evaluate the efficacy and safety of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by standard of care antihypertensive medications.

The primary endpoint of KARDIA-2 is the change from baseline in 24-hour mean systolic blood pressure (SBP) after three months of treatment, as measured by ambulatory blood pressure monitoring (ABPM). Additional endpoints will include change from baseline in blood pressure at six months and time-averaged reduction of blood pressure as a measure of tonic control. Safety will be assessed throughout the study. KARDIA-2 has been activated at clinical sites in the U.S. and will be conducted at approximately 80 clinical study centers worldwide.

https://finance.yahoo.com/news/alnylam-initiates-kardia-2-phase-120000894.html

FDA Grants Tentative Approval for Liquidia Treprostinil Inhalation Powde

 

• First dry-powder formulation of treprostinil to meet criteria required for FDA approval

• Final FDA approval may occur in October 2022 or earlier upon resolution of on-going litigation

• Conference call and webcast scheduled for today at 9:00 a.m. Eastern Standard Time

 Liquidia Corporation (NASDAQ: LQDA) announced today that the U.S. Food and Drug Administration (FDA) granted tentative approval for YUTREPIA™ (treprostinil) inhalation powder, previously referred to as LIQ861. YUTREPIA is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise ability in adult patients with New York Heart Association (NYHA) Functional Class II-III symptoms. Tentative approval indicates that YUTREPIA has met all regulatory standards for quality, safety and efficacy required for approval in the United States.

Dr. Tushar Shah, Chief Medical Officer of Liquidia, said: “We would like to take the opportunity to thank the patients and investigators who participated in the clinical development of YUTREPIA. The tentative approval for YUTREPIA is another step toward providing an important option for patients with PAH in the U.S. We believe YUTREPIA can improve the limitations of current nebulized therapies by allowing the administration of an expanded dose range of inhaled treprostinil using a proven, convenient, palm-sized device.”

The addressable market for inhaled treprostinil is significant and expected to grow. In 2020, United Therapeutics reported that its nebulized formulation of treprostinil indicated for PAH achieved sales of more than $480 million. The attributes of YUTREPIA including ease-of-use, convenience, direct lung delivery, and higher dosage range may not only make YUTREPIA a preference to nebulized therapy, but also an alternative to oral treatments, and possibly a treatment option to delay the use of parenteral therapies in PAH. There may also be future expansion opportunities for inhaled treprostinil into additional indications.

Webcast and Conference Call
Liquidia will host a webcast and conference call Monday, November 8, 2021, at 9:00 a.m. EST to discuss this regulatory update for YUTREPIA™ (treprostinil) inhalation powder. The live call may be accessed by dialing 1-877-707-8711 (domestic) or 1-857-270-6219 (international) and entering the conference code: 8254404. A live and archived webcast of the webcast will also be available on the Events & Presentations page of the Liquidia website at https://liquidia.com/index.php/investors/events-and-presentations.

https://finance.yahoo.com/news/fda-grants-tentative-approval-liquidia-104500924.html

Regeneron's COVID antibody drug shows protection for up to 8 months

 Regeneron Pharmaceuticals said on Monday a single dose of its antibody cocktail reduced the risk of contracting Covid-19 by 81.6% in the two to eight months period following the drug’s administration in a late-stage trial.

The results showed that antibody therapy, REGEN-COV, has the potential to provide long-lasting immunity from Covid-19 infection, said Myron Cohen, who leads monoclonal antibody efforts for the U.S. National Institutes of Health-sponsored COVID Prevention Network.

Such immunity is particularly important for immunocompromised people and those not responding to vaccines, the company said.

The therapy had previously shown an 81.4% risk reduction during the first month after administration.

During the 8-month assessment period, there were no hospitalizations for Covid-19 in the REGEN-COV group, but in the placebo group 6 such incidents were recorded, Regeneron said.

The U.S. health regulator in July expanded REGEN-COV’s authorization to enable its use as a preventive treatment in people exposed to infected individuals, and those at high risk of such exposure in settings such as nursing homes or prisons.

It was authorized in the United States last November to treat people with mild-to-moderate Covid-19 disease.

https://www.cnbc.com/2021/11/08/regenerons-antibody-drug-shows-protection-against-covid-19-for-up-to-8-months-.html

Anti-SARS-CoV-2 vaccination does not induce formation of autoantibodies

  

View ORCID ProfileChristoph Thurm, Annegret Reinhold,  View ORCID ProfileKatrin Borucki,  View ORCID ProfileSascha Kahlfuss,  View ORCID ProfileEugen Feist,  View ORCID ProfileJens Schreiber,  View ORCID ProfileDirk Reinhold,  View ORCID ProfileBurkhart Schraven

doi: https://doi.org/10.1101/2021.11.01.21265737

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.11.01.21265737v1.full.pdf

Abstract

By the end of 2019 a global pandemic by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) causing the coronavirus disease-19 (COVID-19) has emerged. Yet, COVID-19 represents a significant economic burden to healthcare systems, destabilizes global financial markets and has caused the death of almost 5 million people worldwide. In order to prevent severe disease courses of COVID-19 especially in elderly and to establish collective immunity on the long run, different vaccines have been developed, tested and were approved within a very short time period. In Germany, the first vaccines that have been approved by local authorities were AstraZeneca’s vector virus-based vaccine Vaxzevria and the mRNA vaccines Comirnaty and Spikevax, developed by BioNTech and Moderna, respectively. As it was reported that the novel coronavirus SARS-CoV2 can trigger autoimmunity, it is of significant interest to investigate whether anti-SARS-CoV2 vaccines evoke the formation of autoantibodies and subsequent autoimmunity. Here, we did set out to systematically analyze immune responses after homologous vaccinations with mRNA or vector virus-based vaccines or after heterologous Vector/mRNA vaccinations with respect to anti-COVID-19 immune responses and, in parallel, the development of autoantibodies. In our study, we obtained serum samples one day before and 14 as well as 28 days following booster vaccination and tested them for anti-SARS-CoV2 antibodies and for autoantibodies against Cardiolipin, Prothrombin, β2-Glycoprotein, cyclic citrullinated peptides (CCP), tissue-transglutaminase (TTG) and anti-nuclear antibodies (ANA). We find that compared to homologous mRNA and heterologous Vector/mRNA vaccination, anti-SARS-CoV2 antibody levels were 90% lower after homologous vector vaccination. Of note, heterologous Vector/mRNA vaccination was found to be more effective than homologous mRNA vaccination in terms of IgM and IgA responses against SARS-CoV2. However, in terms of autoantibody generation, we only detected increases after booster vaccination in participants with already pre-existing autoantibodies. In contrast, vaccinees showing no autoantibody formation before vaccination, did not respond with sustained autoantibody production upon vaccination. Taken together, our study suggests that all used SARS-CoV2 vaccines do not significantly foster autoantibody production over time but provide humoral immunity to SARS-CoV2.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by grants of the state of Saxony-Anhalt (SI2 and SI3).

https://www.medrxiv.org/content/10.1101/2021.11.01.21265737v1

Longitudinal Changes of Cardiac and Aortic Imaging Phenotypes Following COVID-19 in UK

 Wenjia Bai, Betty Raman, Steffen E Peterson, Stefan Neubauer, Zahra Raisi-Estabragh, Nay Aung, Nicholas C Harvey, Naomi Allen, Rory Collins,  

View ORCID ProfilePaul M Matthews

doi: https://doi.org/10.1101/2021.11.04.21265918

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.11.04.21265918v1.full.pdf

Abstract

Case studies conducted after recovery from acute infection with SARS-CoV-2 have frequently identified abnormalities on CMR imaging, suggesting the possibility that SARS-CoV-2 infection commonly leads to cardiac pathology. However, these observations have not been able to distinguish between associations that reflect pre-existing cardiac abnormalities (that might confer a greater likelihood of more severe infection) from those that arise as consequences of infection. To address this question, UK Biobank volunteers (n=1285; 54.5% women; mean age at baseline, 59.8 years old; 96.3% white) who attended an imaging assessment including cardiac magnetic resonance (CMR) before the start of the COVID-19 pandemic were invited to attend a second imaging assessment in 2021. Cases with evidence of previous SARS-CoV-2 infection were identified through linkage to PCR-testing or other medical records, or a positive antibody lateral flow test; n=640 in data available on 22 Sep 2021) and were matched to controls with no evidence of previous infection (n=645). The majority of these infections were milder and did not involve hospitalisation. Measures of cardiac and aortic structure and function were derived from the CMR images obtained on the cases before and after SARS-CoV-2 infection from images for the controls obtained over the same time interval using a previously validated, automated algorithm. Cases and controls had similar cardiac and aortic imaging phenotypes at their first imaging assessment. Changes between CMR imaging measures in cases before and after infection were not significantly different from those in the matched control group. Additional adjustment for comorbidities made no material difference to the results. While these results are preliminary and limited to imaging metrics derived from automated analyses, they do not suggest clinically significant persistent cardiac pathology in the UK Biobank population after generally milder (non-hospitalised) SARS-CoV-2 infection.

Competing Interest Statement

PMM acknowledges consultancy fees from Novartis, Bristol Myers Squibb, Celgene and Biogen He has received honoraria or speakers honoraria from Novartis, Biogen and Roche and has received research or educational funds from Biogen, Novartis, GlaxoSmithKline and Nodthera.

Funding Statement

PMM acknowledges generous personal and research support from the Edmond J Safra Foundation and Lily Safra, a National Institute for Health Research (NIHR) Senior Investigator Award, the UK Dementia Research Institute and the NIHR Biomedical Research Centre at Imperial College London. WB acknowledges support from EPSRC SmartHeart Programme (EP/P001009/1). SEP acknowledges support from the National Institute for Health Research Barts Biomedical Research Centre. NA and ZRE acknowledge support from the NIHR through Academic Clinical Lecturer funding. ZRE was supported by British Heart Foundation Clinical Research Training Fellowship No. FS/17/81/33318. BR and SN acknowledge support from the Oxford NIHR Biomedical Research Centre and the British Heart Foundation. BR is also supported by the British Heart Foundation Oxford Centre of Research Excellence Transition Clinical Intermediate Fellowship (RE/18/3/34214). NCH acknowledges support from the UK Medical Research Council (MRC MC_UU_12011/1), and NIHR Southampton Biomedical Research Centre, University of Southampton, and University Hospital Southampton. RC Is a British Heart Foundation Chairholder.

https://www.medrxiv.org/content/10.1101/2021.11.04.21265918v1

1 in 4 vaccinated people living in households with covid-19 case become infected

 Ingrid Torjesen

doi: https://doi.org/10.1136/bmj.n2638

PDF: https://www.bmj.com/content/375/bmj.n2638.full.pdf

Vaccination reduces but does not eliminate the risk of covid-19 transmission within households, a study published in Lancet Infectious Diseases has found.1 It showed that one in four vaccinated household contacts of a covid-19 positive case became infected compared with 38% of unvaccinated contacts.

Transmission depends not only on the susceptibility of contacts but also on the infectivity of cases, and while vaccination reduced susceptibility of infection, it did not appear to reduce infectivity—the risk of transmission to vaccinated contacts was similar regardless of whether the index case was vaccinated or unvaccinated.

The study followed 205 household contacts of people confirmed covid-19 positive for the delta variant by polymerase chain reaction (PCR) tests and who experienced mild symptoms or were asymptomatic. Most household contacts (62%) had been doubly vaccinated, 19% had received one vaccine dose, and 19% were unvaccinated. Contacts provided swabs for PCR testing daily for 14-20 days.

Some 53 of the 205 household contacts returned a positive PCR test during the study, including 31 of 126 who were doubly vaccinated (25%) and 15 of the 40 unvaccinated contacts (38%).

The median length of time since vaccination was 101 days among vaccinated contacts infected, compared with 64 days for uninfected contacts, which suggests that protection begins to wane earlier than expected, the researchers told a press conference on 28 October.

Ajit Lalvani, chair of infectious diseases, and director of the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, said, “What we found, surprisingly, was that by three months after the second vaccine dose, the risk of acquiring infection was high compared with being more recently vaccinated. This suggests that vaccine induced protection is already waning by about three months after the second dose.”

Asked whether boosters should be brought forward in light of the findings, Neil Ferguson, director of the MRC Centre for Global Infectious Disease Analysis, Imperial College London, said, “Six months is an arbitrary cut-off. It was chosen because most of the early data from Israel on the effect of boosters involve that level of delay.” He added, “Biologically, there’s nothing to make us think the boosters will be any less effective if given after four months. It is for the Joint Committee on Vaccination and Immunisation to consider the data and the government to consider whether they want to accelerate the booster programme.”

PCR data for some of the participants was used to model their daily viral load trajectories. This revealed that viral load declined more rapidly among vaccinated people compared with those who were unvaccinated, but that there appeared to be no difference in the peak viral load of vaccinated and unvaccinated people.

“The most statistically significant data point is that vaccinated people certainly have a faster rate of viral decline,” said Ferguson, “so they may potentially be infectious for less time, but they don’t necessarily have any reduced peak of viral load. Most transmission probably happens around that peak of viral load, which is why we think we’re still seeing substantial transmission rates from vaccinated people, both to unvaccinated people and to other vaccinated people.”

Lalvani said the faster rate of decline in viral load in vaccinated people helped explain why they get fewer symptoms, quicker resolution of symptoms, and—crucially—have much lower risk of developing severe disease. The modelling showed, however, that vaccination did not affect the time people spent “in the window of highest infectiousness” during peak viral load, and only partially prevented transmission of the delta variant, he added. “This means that unvaccinated people cannot therefore rely on the immunity of the vaccinated population for protection, they remain susceptible to infection, and risk of serious illness and death.”

https://www.bmj.com/content/375/bmj.n2638