TPOXX® (Tecovirimat) Clinical Trials, Dosage, Efficacy, Side Effects
SIGA Technologies, Inc. TPOXX® (tecovirimat, ST-246®), a novel small-molecule oral drug that inhibits the variola virus's and other poxviruses' viral maturation by preventing the formation of a secondary viral envelope (protein F13). Without this envelope, viral particles remain inside the cell and cannot spread to and infect other cells. Tecovirimat is 77-82% bound to human plasma proteins. Tecovirimat is an inducer of cytochrome P450 (CYP) 3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates of those enzymes based on the magnitude of interactions and the duration of treatment of TPOXX.
Tecovirimat's efficacy for treating smallpox was established based on the U.S. Food and Drug Administration (FDA) Animal Rule data and safety data in 359 healthy adults. TPOXX has been approved (July 13, 2018) by the FDA, Canada, the U.K., and the European Medicines Agency (EMA) to treat smallpox. In January 2022, the EMA and the U.K. approved Tecovirimat with a broader label that covers the treatment of smallpox, mpox, cowpox, and complications from vaccination for smallpox. On May 30, 2022, the World Health Organization (WHO) confirmed that TPOXX was effective against mpox infections.
On August 15, 2024, the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) announced topline results from a preliminary analysis of the PALM 007 (Tecovirimat for Treatment of Monkeypox Virus) phase 2 clinical trial (NCT05559099). NIAID reported that the study did not meet its primary endpoint of a statistically significant improvement in time to lesion resolution within 28 days post-randomization for patients in the Democratic Republic of the Congo with mpox who were administered tecovirimat. However, a meaningful improvement was observed in patients receiving tecovirimat whose symptoms began seven days or fewer before randomization and those with severe or more significant disease. The Company believes these data support further trials to assess the potential benefit of tecovirimat in those who present to medical care soon after mpox symptoms and those with severe disease.
On September 13, 2024, the Original Article—Tecovirimat Use under Expanded Access to Treat Mpox in the United States, 2022–2023—published by NEJM Evidence concluded, 'The returned EA-IND data suggest that life-threatening or protracted infections occurred in persons who were severely immunocompromised. The EA-IND data are not definitive; controlled clinical trial data are essential to elucidating if and how tecovirimat should be used.'
As of September 17, 2024, the U.S. Centers for Disease Control and Prevention (CDC) says Tecovirimat is the first-line antiviral treatment recommended for severe mpox or persons with mpox at risk for severe disease. Tecovirimat is FDA-approved only for the treatment of smallpox in adults and children. Using tecovirimat for treating other orthopoxvirus infections, including mpox, is unapproved. On June 9, 2023, the CDC suggested postexposure prophylaxis should be considered for all household members, including children and infants, when mpox is diagnosed. However, the safety and efficacy of TPOXX for treating mpox have not been established. The CDC published - Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug Protocol on September 15, 2022. The CDC/FDA expanded TPOXX access via the Investigational New Drug Protocol. Its use follows Informed Consent. The FDA suggested that the broad use of TPOXX could promote resistance and render the drug ineffective for some patients. The CDC hosted a COCA call on October 6, 2022, and presented: Situational Update for Clinicians about Severe Mpox Virus Infections. The CDC Health Alert Network (HAN) issued CDCHAN-00481 on November 17, 2022, offering clinicians and public health officials information about managing mpox in patients requiring therapeutics. TPOXX treatment for mpox is available through voluntary participation in https://www.stomptpoxx.org/stompsites, sponsored by the U.S. NIH.
Tecovirimat - NDC Code(s): 50072-200-42. DrugBank Accession Number: DB12020. UNII: F925RR824R. ATC code: J05AX24. KEGG: D09390, as monohydrate: D11557. ChEMBL: ChEMBL1257073. Formula: C19H15F3N2O3. ND No. 116,039, CDC IRB No. 6402.
SIGA Technologies, Inc. (NASDAQ: SIGA) is a commercial-stage pharmaceutical company based in New York (31 East 62nd Street, 10065). Net product revenue for the second quarter of 2024 was approximately $2.2 million, and as of June 30, 2024, Tonix had $4.2 million of cash and cash equivalents.
TPOXX Availability United States
Access to tecovirimat remains available through STOMP as the primary route. It is also available under CDC’s EA-IND protocol for patients who meet eligibility criteria. Informed consent is required before treatment. On June 20, 2024, the U.S. CDC reported using emergency preparedness plans. Los Angeles County, June 2022–January 2023, developed a hub and spoke tecovirimat distribution network, facilitating the treatment of approximately one-third of patients with mpox. Most were treated in clinics and pharmacies.
TPOXX Sales And Deliveries
SIGA established a network with over 20 partners across discovery, pre-clinical, clinical, manufacturing, and supply chains that supported the development of TPOXX and the successful delivery of approximately $200 million of courses to the U.S. Strategic National Stockpile (SNS). On July 22, 2024, the U.S. Department of HHS exercised a procurement option for the delivery of approximately $113 million of oral TPOXX® treatment courses.
On June 17, 2024, SIGA announced an agreement to expand access to TPOXX to the member states in the Association of Southeast Asian Nations. On April 1, 2024, SIGA Technologies announced that it entered into an amendment to its international promotion agreement with Meridian Medical Technologies, Inc. Effective June 1, 2024, SIGA will drive international promotion activities for oral TPOXX® while maintaining its contractual relationship with Meridian to maintain continuity for key customer relationships.
In 2023, SIGA had $131 million in product sales, including approximately $98 million of fourth quarter product sales of oral TPOXX to the U.S. SNS, roughly $11 million of product sales of oral TPOXX to the U.S. DoD, of which approximately $6 million was recognized in the fourth quarter; and approximately $21 million of international sales, of which roughly $12 million was recognized in the fourth quarter. In the first two months of 2024, the Company delivered an additional approximately $15 million of oral TPOXX to the U.S. SNS, substantially completing the oral TPOXX order received in July 2023, as well as delivered an additional roughly $7 million of oral TPOXX to European countries and Canada.
On August 9, 2022, SIGA Technologies announced the exercise of procurement options under its 75A50118C00019 (19C) contract with the U.S. HHS to deliver intravenous (IV) formulation of TPOXX treatment courses valued at approximately $26 million. Product deliveries of IV TPOXX in connection with these contract options are targeted for 2023. September 29, 2022, SIGA Technologies announced that the U.S. DoD awarded a new contract for procures to $10.7 million of oral TPOXX (Contract number: W911SR22C0051), of which $5.1 million of oral TPOXX is targeted for delivery in 2022. The remainder is subject to an option at the sole discretion of the DoD. This contract follows an award made earlier this year for the procurement of $7.4 million of oral TPOXX (Contract number: W911SR22C0032), under which all product is expected to be delivered in 2022.
In September 2018, SIGA signed a contract with the U.S. Biomedical Advanced Research and Development Authority (BARDA) for additional procurement and development related to oral and intravenous formulations of TPOXX. SIGA has also collaborated with the Department of Defence (DoD) Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) to develop the Post post-exposure prophylaxis (PEP) indication for TPOXX. The DoD drafted an Expanded Access Protocol (EAP) for TPOXX, which can be used for PEP purposes for certain DoD-affiliated personnel. In addition, oral TPOXX is supplied to the Canadian Department of National Defence and the Public Health Agency of Canada for stockpiling as an essential countermeasure.
TPOXX Mpox Effectiveness and Breakthrough Infections
A small study published in January 2024 suggested that early tecovirimat initiation may hasten subjective symptomatic improvement in people with severe mpox. However, more extensive randomized trials are needed to evaluate this finding. The Antimicrobial Agents Chemotherapy journal published a letter on June 20, 2023, identifying Tecovirimat Resistance-Associated Mutations in Human Monkeypox Virus in Los Angeles County. This analysis detected TPOXX resistance-related HIV status.
The U.S. CDC published Notes from the Field on April 28, 2023, describing patients in New York City diagnosed with mpox who also developed new lesions after completing tecovirimat treatment, suggesting post-treatment lesions might occur more commonly than previously reported by the CDC. In addition, the CDC reported on September 9, 2022, among 317 patients with available outcome information, 230 (72.6%) recovered with or without sequelae by or before completion of the post-treatment assessment; 87 (27.4%) patients were reported by clinicians to be not yet recovered, 78 of whom had not yet completed the standard 14-day tecovirimat treatment course. The CDC's MMWR was published on September 9, 2022. At the post-treatment follow-up visit, it was confirmed that three (2.2%) of 137 persons with information available had developed new lesions compared with 25 (13.1%) who had developed new lesions during the first week of treatment. Most (119, 89.5%) patients reported that all lesions were crusted and healing with a new layer of skin under the scab following treatment.
August 18, 2022, the Annuals of Internal Medicine published: Monkeypox Virus–Associated Severe Proctitis Treated With Oral Tecovirimat (TPOXX): A Report of Two Cases. In summary - Although the direct effect of tecovirimat in precipitating the rapid alleviation of these patients' symptoms cannot be determined. We believe that early use of tecovirimat should be considered for patients with mpox and severe proctitis until randomized controlled trials of tecovirimat can be done.
TPOXX, Mpox, and HIV
JAMA Internal Medicine published a study on January 8, 2024, demonstrating that people with HIV (PWH) who receive tecovirimat within seven days of mpox symptom onset were 13 times less likely to progress to severe mpox disease compared with those who were treated after seven days or who did not receive tecovirimat. These researchers wrote that the findings of this study support the use of tecovirimat in all PWH as soon as mpox is suspected. In a U.S. NIH-funded retrospective study published on May 2, 2023, a cohort of New York City patients treated with tecovirimat for severe mpox, HIV status did not appear to affect treatment outcomes. As of March 3, 2023, the STOMP Trial is evaluating the use of TPOXX in the HIV community.
TPOXX Tecovirimat Resistance
On November 19, 2023, the U.S. CDC's Emerging Infectious Disease - Volume 29, Number 12—December 2023 - confirmed the MPXV F13L gene homologue encodes the target of tecovirimat and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance and 13 novel mutations. The resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment. In contrast, most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive.
This Annals of Internal Medicines report (July 2023) - Tecovirimat Resistance in an Immunocompromised Patient With Mpox and Prolonged Viral Shedding - confirms the potential rapid selection of resistant mutant virus during tecovirimat monotherapy, and we believe this report is the first to study this phenomenon longitudinally. A variant (VP37 N267D) with substantiated tecovirimat resistance was selected within the standard 2-week treatment.
TPOXX Ingredients
Tecovirimat Formula: C19H15F3N2O3; ChemSpider ID: 17281586; ChEMBL Id: 1257073; PubChem CID: 16124688; Monoisotopic mass376.103485 Da. The capsules include the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell comprises gelatin, FD&C blue #1, FD&C red #3, FD&C yellow #6, and titanium dioxide.
TPOXX For Children
The U.S. CDC's MMWR on June 9, 2023 - Notes from the Field: Exposures to Mpox Among Cases in Children Aged ≤12 Years — United States, September 25–December 31, 2022- When caring for the child with mpox, postexposure prophylaxis should be considered for all members of the household. On August 4, 2022, the CDC confirmed that no clinical studies had been done in pediatric populations regarding TPOXX use.
TPOXX For Women
On May 18, 2023, the CDC confirmed insufficient data on TPOXX in women. However, on January 6, 2023, a CDC Morbidity and Mortality Weekly Report disclosed four pregnant women were hospitalized for mpox and administered tecovirimat, which was tolerated with no adverse reactions.
TPOXX Side Effects
The JAMA Network published a Research Letter on August 22, 2022: Compassionate Use of Tecovirimat for Treating Monkeypox Infection. In this preliminary, limited study, oral tecovirimat was well tolerated by all patients with mpox infection, with minimal adverse effects. The safety of TPOXX was evaluated in three clinical trials in 359 healthy adult subjects ages 18-79 years. Of the subjects who received at least one 600 mg dose of TPOXX, 59% were female, 69% were White, 28% were Black/African American, 1% were Asian, and 12% were Hispanic or Latino. Ten percent of the subjects who participated in the study were aged 65 or older. Of these 359 subjects, 336 received at least 23 of 28 doses of 600 mg TPOXX twice daily for 14 days. The most frequently reported adverse reactions were headaches and nausea. Adverse reactions occurred in at least 2% of the TPOXX treatment group subjects. In addition, co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia.
TPOXX Drug Interactions
Significant interactions have been reported in healthy adults with co-administration of repaglinide (hypoglycemia) and midazolam (decreased effectiveness of midazolam).
TPOXX Price
The U.S. CDC confirmed on August 18, 2022, that healthcare providers could provide tecovirimat (TPOXX) treatment to patients with mpox under EA-IND. The drug is currently offered at no cost. Contact the CDC Emergency Operations Center (770-488-7100) for clinical consultation on patient cases. NYC providers who want to prescribe tecovirimat and adhere to the IND protocol can email [email protected] for information on free delivery to patients or request supplies for a pharmacy at their facility.
TPOXX News
March 13, 2024 - "In 2023, SIGA had approximately $131 million in product revenues and approximately $84 million of pre-tax operating income," stated Diem Nguyen, Chief Executive Officer. "These financial results represent a significant increase over the 2022 financial results; product revenues increased 51% over the corresponding 2022 amount, and pre-tax operating income year increased 96% over the corresponding 2022 amount.
April 28, 2023—The U.S. CDC published Notes from the Field: Post-treatment Lesions After Tecovirimat Treatment for Mpox—New York City, August–September 2022. New lesions appeared a median of 13 days after completion of Tecovirimat treatment (range = 2–30 days). In eight patients, the provider rated post-treatment lesions as less severe than initial lesions (median severity score = 3 [range = 3–7]).
February 2, 2023 - Special Report: Overview of the regulatory approval of tecovirimat intravenous formulation for treating smallpox: potential impact on smallpox outbreak response capabilities, and future tecovirimat development potential.
September 6, 2022—The HHS Administration for Strategic Preparedness and Response awarded AmerisourceBergen a distribution contract valued at $19.8 million to expand MPXV treatment access.
August 25, 2022 - The Swiss government health agency (SwissMedic) intends to purchase 500 units of the TPOXX antiviral.
July 15, 2022 - SIGA Technologies announced a collaboration with KaliVir Immunotherapeutics to make TPOXX® available for use with KaliVir's novel oncolytic vaccinia immunotherapy platform, including multiple proprietary genetic modifications that can be combined to generate a unique oncolytic virus that has been optimized for systemic delivery and anti-tumor immune stimulation.
May 19, 2022 - SIGA Technologies, Inc. announced that the U.S. FDA approved the IV formulation of TPOXX for treating smallpox.
January 10, 2022 - SIGA Technologies, Inc. announced that the EMA approved SIGA's Marketing Authorisation Application for oral tecovirimat. The EMA approval includes labeling for oral tecovirimat, indicating its use to treat smallpox, mpox, cowpox, and vaccinia complications following vaccination against smallpox.
July 29, 2021 - SIGA Technologies, Inc. announced that it has partnered with Oxford University in the U.K. to provide TPOXX® (tecovirimat) under an expanded access protocol to treat individuals affected by mpox in the Central African Republic.
July 13, 2018 - The U.S. FDA approved TPOXX (tecovirimat), the first drug with an indication for the treatment of smallpox. The FDA granted this application Fast Track and Priority Review designations, and TPOXX also received an Orphan Drug designation.
TPOXX Clinical Trials
The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, is sponsoring the Study of Tecovirimat for Human Mpox Virus (STOMP). The STOMP trial assesses whether tecovirimat is safe and effective for treating mpox in people with the disease.
A Phase 3 clinical trial evaluating the antiviral tecovirimat, also known as TPOXX, began enrolling adults and children with monkeypox infection in the United States on September 9, 2022. Study investigators aim to register more than 500 people from clinical research sites nationwide. Interested volunteers can visit the ACTG website (clinical trial A5418) for more information. The National Institute of Allergy and Infectious Diseases sponsors the trialThe first study compares the enrolled participants' immune response to the Jynneos smallpox vaccines to the immune response to Jynneos while on TPOXX treatment. In addition, the study is designed to determine if TPOXX interferes with developing an effective immune response to the vaccine. A second clinical study, also expected to commence in 2022, will look at creating an expanded safety dataset to support 28-day dosing of TPOXX for the post-exposure prophylaxis indication compared with the currently approved 14 days for treatment of smallpox indication.
