TPOXX® (Tecovirimat) Smallpx Mpox Antiviral June 2023
SIGA Technologies, Inc. TPOXX® (tecovirimat, ST-246®), a novel small-molecule 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.
TPOXX was approved in the U.S. (July 13, 2018) by the U.S. Food and Drug Administration (FDA), Canada, the U.K., and the European Medicines Agency (EMA) to treat smallpox. Tecovirimat's efficacy for treating smallpox was established based on the FDA Animal Rule.
In September 2018, SIGA signed a contract with the 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 Exposure Prophylaxis (PEP) indication for TPOXX. This DoD work is supported by a separate development contract (Sept. 2020) of approximately $26 million. As a result, the DoD has 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. And in January 2022, the EMA approved Tecovirimat with a broader label that covers the treatment of smallpox, mpox, cowpox, and complications from vaccination for smallpox. In addition, the World Health Organization (WHO) confirmed on May 30, 2022, that TPOXX is effective against a mpox virus infection.
The CDC/FDA expanded TPOXX access via the Investigational New Drug Protocol. Its use follows Informed Consent. The U.S. CDC published - Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug Protocol on September 15, 2022. The FDA suggested 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. On December 15, 2022, the NEJM published a Correspondence reported by the final study visit that 12 of 13 patients were PCR-negative and had recovered; scarring was visible in 9 patients. The median time from the initiation of treatment until the absence of active lesions was five days.
On May 18, 2023, the CDC confirmed TPOXX is approved by the FDA for treating human smallpox, but not mpox. It may be used for non-variola orthopoxvirus infection (e.g., mpox) under a CDC-held Expanded Access Investigational New Drug Protocol for adults and children weighing at least 3 kg. And Mpox postexposure prophylaxis efficacy is unstudied.
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 New York-based (31 East 62nd Street, 10065) commercial-stage pharmaceutical Company focused on the health security market.
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 Effectiveness and Breakthrough Infections
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. confirmed at the post-treatment follow-up visit, 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 and HIV
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 Availability 2023
SIGA established a network with over 20 partners across discovery, pre-clinical, clinical, manufacturing, and supply chain that supported the development of TPOXX and the successful delivery of approximately $200 million of courses to the U.S. Strategic National Stockpile (SAs a result, NS). As a result, TPOXX is available in the United Kingdom, Canada, and Europe. As of 2022, the SNS had over 1.7 million treatment courses of TPOXX, which can be used to treat individuals with monkeypox under an appropriate regulatory mechanism. The U.S. federal public health emergency expired on January 31, 2023. However, HHS remains committed to making TPOXX available to those who qualify for treatment addition; TPOXX treatment for mpox is available through voluntary participation in https://www.stomptpoxx.org/stompsites, sponsored by the U.S. NIH.
On August 9, 2022, SIGA Technologies announced the exercise of procurement options under its 75A50118C00019 (19C) contract with the U.S. HHS foto 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.
The Company announced on September 26, 2022, the receipt of approximately $16 million of international procurement orders for TPOXX in August and early September 2In addition, 022. SIGA has received approximately $76 million of international orders for oral TPOXX from 12 international customers. It is suspected that at least $65 million of these orders will be delivered in 2022.
And on September 29, 2022, SIGA Technologies announced that the U.S. DoD awarded a new contract foto 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.
TPOXX For Children
The U.S. CDC confirmed on August 4, 2022, 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 359 healthy adult subjects ages 18-79 years in an ase three clinical trials. 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 Revenues
On May 4, 2023, based on the anticipated expiration of significant quantities of TPOXX held within the U.S. Government's Strategic National Stockpile ("SNS"), the Company is targeting approximately $113 million of oral TPOXX deliveries to the SNS.
The Company reported on March 2, 2023, that in 2022, SIGA received approximately $77 million of international orders for oral TPOXX (tecovirimat) from 13 customers, of which 12 were new customers in 2022. Roughly $71 million of these orders were delivered and recorded as international sales in 2022.
SIGA Technologies, Inc. announced on June 23, 2022, approximately $13 million of procurement orders for oral TPOXX (tecovirimat), including $11 million for initial procurement from two new international jurisdictions and an approximate $2 million order from a country in the Asia Pacific region.
As of March 31, 2022, the Company's contract with BARDA contemplates up to approximately $602.5 million of payments, of which approximately $51.7 million of payments are included within the base period of performance of five years, approximately $239.7 million of payments are related to exercised options and up to approximately $311.1 million of payments are currently specified as unexercised options.
TPOXX News
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]). One received a positive result among six patients for whom orthopoxvirus testing of post-treatment lesions was conducted. Two patients received repeat STI testing; one received a positive syphilis test result. The immunocompromised patient with untreated HIV received positive post-treatment orthopoxvirus and positive syphilis test results.¶ Tecovirimat was restarted for two patients (one treated for seven additional days and one treated for 14 additional days), both of whom had resolved their lesions. Among the seven patients who did not receive a second course of tecovirimat, six had a resolution of lesions, and one was lost to follow-up.
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.
October 12, 2022 - NIAID Director Anthony S. Fauci, M.D., said in a press release, "This phase 2 clinical trial (in the DRC) will yield critical information about the safety and efficacy of tecovirimat for monkeypox. The drug targets a protein in both the virus that causes smallpox and the MPXV.
October 3, 2022 - The AMA published: What physicians should know about using TPOXX to treat monkeypox.
September 29, 2022 - "We are pleased to continue our growing relationship with DoD, which encompasses, among other things, providing oral TPOXX to support the warfighter against orthopoxvirus risks such as smallpox and monkeypox and working closely with DoD on the continued development of the PEP indication for oral TPOXX," said Phil Gomez, CEO of SIGA." The Company's New Contract Awarded by U.S. DOD is for the Procurement of up to $10.7 Million of Oral TPOXX.
September 26, 2022 - Phil Gomez, CEO of SIGA, commented: "Procurement of TPOXX by the European Commission and by individual countries represent important steps in addressing the near-term risks of the monkeypox outbreak and toward acknowledging and preparing for the longer-term risks posed by the family of orthopoxviruses."
September 9, 2022 - The CDC published: Clinical Use of Tecovirimat (TPOXX) for Treatment of Monkeypox Under an Investigational New Drug Protocol — United States, May-August 2022. Tecovirimat is generally well tolerated, and these data support continued access to treatment with tecovirimat during the current monkeypox outbreak.
September 9, 2022 - The U.S. NIH announced a phase 3 clinical trial (A5418) of tecovirimat in the United States led by Timothy Wilkin, M.D., professor of medicine at Weill Cornell Medicine in New York City, NY, is enrolling adults and children with monkeypox in the trial.
September 6, 2022 - The HHS Administration for Strategic Preparedness and Response awarded a distribution contract to AmerisourceBergen, 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.
August 23, 2022 - The team behind the world-leading RECOVERY trial is leading a new study investigating a potential treatment for people diagnosed with monkeypox. In PLATINUM, participants will be randomly allocated to receive either a 14-day course of 600 mg tecovirimat twice daily or a matched placebo treatment, with participants taking the medicine placebo in their homes.
August 18, 2022 - The NEJM published - Perspective: Tecovirimat and the Treatment of Monkeypox — Past, Present, and Future Considerations.
August 11, 2022 - "There are currently no data demonstrating the effectiveness of Tpoxx for thtreatingmallpox or monkeypox in humans. Tpoxx has only been tested in healthy human volunteers, without smallpox or monkeypox infection, to assess safety," the spokesperson told Bloomberg Law.
August 9, 2022 - The Company issued a press statement: "These option exercises for the procurement of IV formulation of TPOXX as well as the funding of a post-marketing field study for IV TPOXX h, light the growing importance of a broad-based response to the substantial risks posed by the orthodox family of viruses, including smallpox and monkeypox," said Phil Gomez, CEO of SIGA.
August 3, 2022 - ThThe U.S. CDC published the Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug ProtocolAugust 3, 2022 - The NEJM reported officials at the U.S. FDA, CDC, and NIH confirm human clinical studies are needed, even as TPOXX's access becomes more accessible
July 29, 2022 - The U.S. FDA confirmed no FDA-approved or authorized medicine for thtreatingonkeypox disease. TPOXX is being made available in the USA under an FDA authority called Expanded Access or "compassionate use."
July 22, 2022 - According to CNN, two children are being treated with TPOXX, an antiviral recommended by the U.S. CDC for children under age.
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 t, 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.
July 14, 2022 - The AMA published: Monkeypox numbers, treatment, and prevention with two CDC experts. AMA's Moving Medicine video series amplifies physician voices and highlights medical developments and achievements
July 12, 2022 - SIGA Technologies, Inc. announced approximately $28 million of procurement orders for oral TPOXX® (tecovirimat), including approximately $2 million for initial procurement by two new international jurisdictions and approximately $26 million for procurement by Canada, of which approximately $22 million is being procured by the Public Health Agency of Canada and approximately $4 million is being procured by the Canadian Department of National Defence under existing contracts. One of the new jurisdictions is in Europe, and the other new jurisdiction is in the Asia Pacific region. In combination with the approximately $13 million PHAC order previously disclosed on the last investor call, PHAC and DND have ordered approximately $39 million of oral TPOXX (tecovirimat) this year.
June 23, 2022 - SIGA Technologies, Inc. announced Phil Gomez, CEO, stated, "We expect a portion of the courses of oral TPOXX delivered under these (new) orders will be used for the treatment of active monkeypox cases and represent the first step in response to this outbreak by the global public health community. By increasing the scale and scope of TPOXX stockpiling, countries can be better prepared for the outbreak risks of smallpox, monkeypox, and other viruses in the orthopoxvirus family and make sure that patients can access a proven safe and effective treatment."
May 27, 2022 - Reuters reported the E.U. is collaborating on a common purchasing agreement for monkeypox virus antivirals.
May 24, 2022 - The Lancet Infectious Disease published: Clinical features and management of human monkeypox: a retrospective (2018-2021) observational study in the U.K. The patient was given 200 mg of oral tecovirimat twice daily for two weeks, had no adverse effects, and shed viral DNA for only ten days. 'We report the first use of antiviral agents in patients with monkeypox, with one receiving tecovirimat. The patient treated with tecovirimat had a shorter duration of symptoms and upper respiratory tract viral shedding than the other patients in the series; adverse events were identified before discharge. However, several patients experienced prolonged viremia and upper respiratory tract viral shedding after crusting of all cutaneous lesions, leading to extended isolation in the hospital.
May 19, 2022 - SIGA Technologies, Inc. announced that the U.S. FDA approved the intravenous (IV) formulation of TPOXX for treating smallpox. The IV formulation is an essential option for those unable to swallow the oral capsules of TPOXX.
May 12, 2022 - SIGA Technologies, Inc. announced that the U.S. DoD awarded a contract to SIGA to procure up to approximately $7.5 million of oral TPOXX. Roughly $3.6 million of oral TPOXX is targeted for delivery in 2022. The remainder is subject to an option at the sole discretion of the DoD.
May 5, 2022 - SIGA Technologies CEO Phil Gomez stated: "With the first quarter of $7 million of IV TPOXX to the U.S. government, SIGA has expanded its TPOXX revenue base in the U.S. On the international front, the revenue base is expanding with a new contract with jurisdiction in the Asia Pacific region. Under the new contract, approximately $3 million of oral TPOXX has been ordered for delivery in 2022."
May 2, 2022 - SIGA announced that it had initiated a clinical program to support a U.S. FDA label expansion for Post-Exposure Prophylaxis for oral TPOXX.
April 8, 2022 - The U.S. CDC's MMWR reported, 'The patient completed a 32-day hospitalization that included treatment with tecovirimat because of severe disease. Hospital discharge had been delayed until a remaining lesion tested negative for Monkeypox virus DNA.'
January 10, 2022 - SIGA Technologies, Inc. announced that the European Medicines Agency (EMA) approved SIGA's Marketing Authorisation Application (MAA) for oral tecovirimat. The U.S. FDA approved the same formulation in July 2018 under the brand name TPOXX®. The EMA approval includes labeling for oral tecovirimat, indicating its use to treat smallpox, monkeypox, cowpox, and vaccinia complications following vaccination against smallpox. The MAA enables sales in European Union member states, Norway, Iceland, and Liechtenstein.
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 monkeypox in the Central African Republic.
July 13, 2018 - The U.S. Food and Drug Administration 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. TPOXX also received Orphan Drug designation.
TPOXX Clinical Trials
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 enregisterore 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.
