TPOXX® (Tecovirimat) Description
SIGA Technologies, Inc. TPOXX® (tecovirimat, ST-246®), a novel small-molecule drug.TPOXX inhibits the viral maturation of the variola virus and other poxviruses, such as monkeypox, 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 a weak 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 is approved in the USA (2018), Canada, U.K., and Europe to treat smallpox, and recently for monkeypox. Later, the European Medicines Agency (EMA) and the Norwegian Medicines Agency approvals include the treatment of monkeypox, cowpox, and complications from immunization with vaccinia. Tecovirimat's efficacy for the treatment of smallpox was established and was approved, based on the U.S. FDA Animal Rule, in studies in animal models using related orthopoxviruses, specifically, nonhuman primates infected with monkeypox virus and rabbits infected with rabbitpox virus. TPOXX was approved as oral capsules targeted against smallpox by the U.S. FDA on July 13, 2018.
In September 2018, SIGA signed a contract with the Biomedical Advanced Research and Development Authority (BARDA) for additional procurement and development related to both oral and intravenous formulations of TPOXX. SIGA has also collaborated with the DoD's 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.
Following U.S. approval, Health Canada authorized oral TPOXX for treating human smallpox disease in people weighing at least 13 kg in November 2021. 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 (TPOXX) with a broader label that covers the treatment of smallpox, monkeypox, cowpox, and complications from vaccination for smallpox. The World Health Organization (WHO) confirmed on May 30, 2022, that TPOXX is effective against a monkeypox virus (MPX) infection.
In the USA, there are no FDA-approved treatments for monkeypox; however, TPOXX (tecovirimat) is being made available through a randomized controlled clinical trial sponsored by the National Institutes of Allergy and Infectious Diseases and also through the CDC under an FDA authority called Expanded Access, or “compassionate use.” On May 19, 2022, the FDA approved the intravenous (IV) formulation of TPOXX. In addition, on August 3, 2022, the U.S. CDC published Guidance for Tecovirimat use under the Expanded Access Investigational New Drug Protocol (EA-IND). The CDC holds a non-research EA-IND protocol that allows for the use of tecovirimat for primary or early empiric treatment of non-variola orthopoxvirus infections, including monkeypox, in adults and children of all ages. And on August 9, 2022, the HHS Secretary issued a 564 determination, paving way for emergency use authorization of monkeypox treatments. On September 9, 2022, the U.S. CDC confirmed for patients treated under the EA-IND protocol and included in this Morbidity and Mortality Weekly Report, the median time to subjective improvement was three days after receiving tecovirimat. However, no control group was available for comparison; therefore, the CDC says 'no conclusions can be drawn regarding the effectiveness of tecovirimat to treat monkeypox based on these data.'
The CDC/FDA expanded access to the Investigational New Drug Protocol for TPOXX. Its use follows Informed Consent. The U.S. CDC published - Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug Protocol during the 2022 U.S. Monkeypox Outbreak on September 15, 2022. Based on data from published literature and the FDA, which suggest that broad use of the antiviral drug TPOXX could promote resistance and render the drug ineffective for some patients. For most patients with healthy immune systems, supportive care and pain control may be enough. However, Tecovirimat should be considered for use in people who have the following clinical manifestations: Severe disease, Involvement of anatomic areas, which might result in serious sequelae that include scarring or strictures, and Tecovirimat should also be considered for use in people who are at high risk for severe disease.
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.
On August 18, 2022, the FDA highlighted: Tecovirimat and the Treatment of Monkeypox – Past, Present, and Future Considerations. And the FDA confirmed on July 29, 2022, that there is currently no human data demonstrating the efficacy of TPOXX for the treatment of monkeypox or the safety and pharmacokinetic profile.
TPOXX (Tecovirimat) Price
The U.S. CDC confirmed on August 18, 2022, that healthcare providers could provide tecovirimat (TPOXX) treatment to patients with monkeypox under EA-IND. The drug is currently provided 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 can 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.
The CDC's Vaccines For Children program is a federally funded program that provides vaccines and medicines at no cost to children. And InstantRx™ is a digital gateway empowering people to easily find lower-priced medicines and vaccines.
SIGA has 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 (SNS). The CDC holds an intermediate-size patient population EA-IND (IND 116,039/Protocol 6402) to allow access to and use of TPOXX for the treatment of orthopoxvirus infections, including monkeypox.
As of July 1, 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. As of September 2, 2022, the SNS had shipped more than 37,000 courses of TPOXX in the USA. On August 18, 2022, the U.S. HHS confirmed it would be pre-positioning 50,000 courses of TPOXX across the USA.
On August 9, 2022, SIGA Technologies announced the exercise of procurement options under its 75A50118C00019 (19C) contract with the U.S. HHS for the delivery of 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.
As of August 1, 2022, the U.S. CDC posted information updating the TPOXX ordering process. Clinicians and healthcare facility pharmacists can request TPOXX preferably by contacting their state or territorial health department; however, they can also reach out directly to CDC by contacting its Emergency Operations Center (EOC, 770-488-7100; [email protected]).
The Company announced on September 26, 2022, the receipt of approximately $16 million of international procurement orders for TPOXX in August and early September 2022. SIGA has received approximately $76 million of international orders for oral TPOXX from 12 international customers. It is currently expected that at least $65 million of these orders will be delivered in 2022. TPOXX is available in the United Kingdom, Canada, and Europe.
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 posttreatment 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.
TPOXX (Tecovirimat) Ingredients
Tecovirimat Formula: C19H15F3N2O3; ChemSpider ID: 17281586; ChEMBL Id: 1257073; PubChem CID: 16124688; Monoisotopic mass376.103485 Da. The capsules include the following 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 Breakthrough Infections
The CDC's MMWR was published on September 9, 2022. confirmed at the time of the posttreatment 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 monkeypox and severe proctitis until randomized controlled trials of tecovirimat can be done.
TPOXX For Children
The U.S. CDC confirmed on August 4, 2022, that Tecovirimat had been used in a 28-month-old child with no adverse effects attributed to the drug, but no clinical studies have been done in pediatric populations. Monitoring of renal function is recommended in pediatric patients < 2 years of age, given theoretical concerns that renal immaturity in young pediatric patients may result in higher exposure to hydroxypropyl-β-cyclodextrin, an ingredient in IV tecovirimat. Animal studies have shown potential for nephrotoxicity at very high exposure levels of hydroxypropyl-β-cyclodextrin.
And on July 26, 2022, that Tecovirimat is the first-line medication to treat monkeypox disease in children and adolescents. However, cases should be considered independently. Information for Healthcare Professionals was published in June 2022.
TPOX For Women
Although tecovirimat has not been studied in pregnant and nursing women, says the U.S. CDC, they are not excluded from treatment if deemed appropriate following careful clinical assessment and discussion of risks/benefits with patients using a shared decision-making model. There are no human data to establish the presence or absence of tecovirimat-associated risk of fetotoxicity, effect on milk production, the presence of drug in human milk, and/or effects on breastfed children. No fetotoxicity was found in animal studies, though tecovirimat was detected in trace amounts in milk.
TPOXX Side Effects
The JAMA Network published a Research Letter on August 22, 2022: Compassionate Use of Tecovirimat for the Treatment of Monkeypox Infection. In this preliminary, limited study, oral tecovirimat was well tolerated by all patients with monkeypox infection, with minimal adverse effects.
The safety of TPOXX was evaluated in 359 healthy adult subjects ages 18-79 years in a Phase 3 clinical trial. 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 subjects received at least 23 of 28 doses of 600 mg TPOXX in a twice-daily regimen 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. Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms when administering TPOXX with repaglinide.
TPOXX Drug Interactions
Significant interactions have been reported in healthy adults with co-administration of repaglinide (hypoglycemia) and midazolam (decreased effectiveness of midazolam).
Use of Tecovirimat under Expanded Access IND
Currently, there is no treatment approved by the U.S. FDA for non-variola orthopoxvirus, including MPX. Although tecovirimat is FDA-approved for the treatment of smallpox in adults and children, the approved indication is limited to smallpox. Therefore, this intermediate-size patient population expanded access to IND, sponsored by the CDC and authorized by the FDA, to allow access to and use of stockpiled tecovirimat for treatment of non-variola orthopoxvirus (NV-OPXV) infection in adults and children. While the effectiveness of tecovirimat in treating human non-variola orthopoxvirus infections, including monkeypox, has not been evaluated, it may be reasonable to anticipate potential treatment benefits based on animal efficacy data that supported FDA approval for smallpox treatment and limited clinical uses of tecovirimat in the treatment of NV-OPXV infected individuals to date.
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.
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 who have been 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 treatment or placebo in their own 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 the treatment of smallpox 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 highlight 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 - The Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug Protocol was published by the U.S. CDC.
August 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 easier.
July 29, 2022 - The U.S. FDA confirmed there is no FDA-approved or authorized medicine for the treatment of monkeypox 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 eight.
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 that includes 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 developments and achievements throughout medicine.
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 that was 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, with no adverse events 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 delivery in 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 entered into a collaboration 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 enroll more than 500 people from clinical research sites nationwide. Interested volunteers can visit the ACTG website (clinical trial A5418) for more information. The trial is sponsored by the National Institute of Allergy and Infectious Diseases.
The first study compares the enrolled participants' immune response to the Jynneos smallpox vaccines to the immune response to Jynneos while on TPOXX treatment. 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 developing 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.