Ulteriore studio del Quad della Gilead

[Dora]

L'Antiviral Drugs Advisory Committee ieri ha votato 13 a 1 a favore dell'approvazione del Quad.
La decisione dell'FDA è attesa entro fine agosto.

Ieri l'FDA ha approvato il Quad: nome commerciale Stribild (elvitegravir, cobicistat, emtricitabina, tenofovir disoproxil fumarate).

FDA approves new combination pill for HIV treatment for some patients

For Immediate Release: Aug. 27, 2012
Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yaoATfda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

The U.S. Food and Drug Administration today approved Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate), a new once-a-day combination pill to treat HIV-1 infection in adults who have never been treated for HIV infection.

Stribild contains two previously approved HIV drugs plus two new drugs, elvitegravir and cobicistat. Elvitegravir is an HIV integrase strand transfer inhibitor, a drug that interferes with one of the enzymes that HIV needs to multiply. Cobicistat, a pharmacokinetic enhancer, inhibits an enzyme that metabolizes certain HIV drugs and is used to prolong the effect of elvitegravir. The combination of emtricitabine and tenofovir disoproxil fumarate, approved in 2004 and marketed as Truvada, blocks the action of another enzyme that HIV needs to replicate in a person’s body. Together, these drugs provide a complete treatment regimen for HIV infection.

“Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research. “New combination HIV drugs like Stribild help simplify treatment regimens.”

Stribild’s approval is the latest HIV/AIDS-related action taken by the FDA this year. Other actions include approval of the first over-the-counter home-use rapid HIV test; approval of the first drug for pre-exposure prophylaxis in combination with safer sex practices to reduce the risk of sexually acquired HIV infection in adults at high risk; and commemoration of the full or tentative approvals of more than 150 antiretroviral products for the President’s Emergency Plan for AIDS Relief (PEPFAR) to treat those in countries most affected by the HIV/AIDS epidemic.

The safety and effectiveness of Stribild was evaluated in 1,408 adult patients not previously treated for HIV in two double-blind clinical trials. Patients were randomly assigned to receive Stribild or Atripla, an HIV drug that contains Truvada and efavirenz, once daily in the first trial; and Stribild or Truvada plus atazanavir and ritonavir once daily in the second trial.

The studies were designed to measure the percentage of patients who had an undetectable amount of HIV in their blood at 48 weeks. Results showed between 88 percent and 90 percent of patients treated with Stribild had an undetectable amount of HIV in their blood, compared with 84 percent treated with Atripla and 87 percent treated with Truvada plus atazanavir and ritonavir.

Like labels of many other drugs used to treat HIV, Stribild’s label carries a Boxed Warning alerting patients and health care professionals that the drug can cause a build up of lactic acid in the blood and severe liver problems, both of which can be fatal. The Boxed Warning also states that Stribild is not approved to treat chronic hepatitis B virus infection.

Common side effects observed in clinical trials include nausea and diarrhea. Serious side effects include new or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome). Stribild’s label gives advice to health care providers on how to monitor patients for kidney or bone side effects.

Gilead Sciences, Stribild’s manufacturer, is required to conduct additional studies to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs.

Gilead Sciences is based in Foster City, Calif.


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Comunicato stampa di Gilead:

U.S. FDA Approves Gilead's Stribild[size=85]™[/size][size=120], a Complete ... Infection[/size]

FOSTER CITY, Calif.--(BUSINESS WIRE)--Aug. 27, 2012-- Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has approved StribildTM (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), a complete once-daily single tablet regimen for HIV-1 infection for treatment-naïve adults. Stribild, referred to as “Quad” prior to FDA approval, combines four compounds in one daily tablet: elvitegravir, an integrase inhibitor; cobicistat, a pharmacoenhancing agent; emtricitabine and tenofovir disoproxil fumarate.

“Over the past decade, co-formulated HIV medicines have simplified therapy for many patients and have become standard of care,” said Paul Sax, MD, Clinical Director of the Division of Infectious Diseases at Brigham and Women’s Hospital, Boston, Professor of Medicine at Harvard Medical School, and principal investigator of one of the Stribild pivotal studies. “Today’s approval of Stribild will provide physicians and their patients an effective new single tablet treatment option for individuals starting HIV therapy for the first time.”

The approval of Stribild is supported by 48-week data from two pivotal Phase 3 studies in which the single tablet regimen met its primary objective of non-inferiority compared to Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (Study 102) and to a regimen containing ritonavir-boosted atazanavir plus Truvada® (emtricitabine/tenofovir disoproxil fumarate) (Study 103). Today’s approval is also supported by Chemistry, Manufacturing and Controls (CMC) information on the individual components of Stribild and the co-formulated single tablet regimen.

“For much of the company’s 25-year history, Gilead has focused on the development of improved treatments and simplified regimens for HIV,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. “Therapies that address the individual needs of patients are critical to enhancing adherence and increasing the potential for treatment success, and we are proud to introduce a new single tablet regimen for the healthcare and patient communities.”

Stribild is the third single tablet HIV regimen developed by Gilead. The first, Atripla, was approved in 2006 and is marketed by Gilead and Bristol-Myers Squibb in the United States. The second single tablet regimen, Complera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), which combines Gilead’s Truvada and Janssen R&D Ireland’s rilpivirine, was approved in 2011.

In all studies of Stribild, most adverse events were mild to moderate. Stribild has Boxed Warnings of lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for important safety information.

Applications for marketing approval of Stribild are also pending in Australia, Canada and the European Union. In the developing world, Gilead has granted multiple Indian manufacturing partners and the Medicines Patent Pool the right to develop generic versions of Stribild and distribute them to 100 developing countries. These agreements include a complete technology transfer of the manufacturing process for the single tablet regimen.

Patient Assistance Programs

Gilead’s U.S. Advancing Access® program provides assistance to patients in the United States who do not have insurance or who need financial assistance to pay for their medications, including Stribild. Patients may contact Advancing Access at 1-800-226-2056 between 9:00 a.m. and 8:00 p.m. (Eastern Time) to see if they are eligible for the program.

For patients with private insurance, Gilead’s co-pay coupon program provides assistance with out-of-pocket expenses for Gilead’s HIV medications, including Stribild, starting at the first dollar. Additionally, Gilead is working closely with the ADAP Crisis Task Force, as the company has done for each of its other HIV medications, to provide discounts to state AIDS Drug Assistance Programs (ADAPs) that will help ensure access to Stribild for patients who receive medications through these programs.

About Stribild

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil fumarate 300 mg. Stribild is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. Stribild does not cure HIV-1 infection.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights. Gilead submitted a New Drug Application (NDA) to FDA for elvitegravir on June 27, 2012.

Cobicistat is a pharmacoenhancing or “boosting” agent that enables elvitegravir once-daily dosing. It is a potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Cobicistat acts only as a pharmacoenhancer and has no antiviral activity. Gilead submitted an NDA to FDA for cobicistat on June 28, 2012.

Elvitegravir and cobicistat as standalone agents are investigational products and their safety and efficacy have not yet been established.

Important Safety Information about Stribild

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (“tenofovir DF”), a component of Stribild, in combination with other antiretrovirals.
Stribild is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Stribild have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Stribild. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Stribild. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications

Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Do not use with drugs that strongly induce CYP3A as this may lead to a loss of virologic response and possible resistance to Stribild. Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, and St. John’s wort.

Warnings and Precautions

New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF and Stribild. Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent.
Use with other antiretroviral products: Stribild should not be coadministered with products containing any of the same active components; with products containing lamivudine; with adefovir dipivoxil; or with products containing ritonavir.
Decreases in bone mineral density (BMD) and cases of osteomalacia have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss.
Fat redistribution and accumulation have been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.

Adverse Reactions

Common adverse drug reactions in clinical studies (incidence greater than or equal to 5%; all grades) were nausea, diarrhea, abnormal dreams, headache and fatigue.

Drug Interactions

CYP3A substrates: Stribild can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Do not use with drugs highly dependent on these factors for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events.
CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of components of Stribild. Do not use with drugs that strongly induce CYP3A as this may lead to loss of virologic response and possible resistance to Stribild.
Antacids: Separate Stribild and antacid administration by at least 2 hours.
Prescribing information: Consult the full prescribing information for Stribild for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

Adult dosage: One tablet taken orally once daily with food.
Renal impairment: Do not initiate in patients with CrCl below 70 mL/min. Discontinue in patients with CrCl below 50 mL/min.
Hepatic impairment: Not recommended in patients with severe hepatic impairment.

Pregnancy and Breastfeeding

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.
Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.

[Puzzle]

Non capisco perché denigrare tanto questo Quad. Io prenderei più che volentieri una pasticca al giorno, e ne ho già parlato alla mia dott per quando sarà approvato anche in Europa.

[Dora]

Io prenderei più che volentieri una pasticca al giorno, e ne ho già parlato alla mia dott per quando sarà approvato anche in Europa.

Temo dovrai aspettare un po', perché pare che il prezzo esorbitante che Gilead prevede di imporre in Europa possa ritardare di non si sa quanto l'approvazione qui da noi. Vedi Quad approved in US: exorbitant cost likely to block use in Europe.

Il ragionamento fatto da Simon Collins potrebbe valere solo per il Regno Unito, ma è ragionevole pensare che finirà con l'estendersi anche all'Italia:

• (...) While drug pricing can be complex, a similar price differential launched in Europe, and certainly in the UK, would see Quad placed securely on the top shelf, where it could perhaps be seen, but would be well out of the reach for all but the wealthiest citizens or health care providers. It is a move that will make it unlikely to find its way into the bloodstream of patients, where it might have been able to demonstrate its marginal level of non-inferiority compared to current options: a non significant 4% difference in the percentage of patients with undetectable viral load after 48 weeks of treatment. While Quad offers potential advantages in care, these were not demonstrated in the clinical trials that led to approval based on finding it is “not likely to be worse” than current treatment. Without demonstrable advantages, public health care providers, including the NHS, are likely to find it difficult to make a case for its routine use.
  
  The annual wholesale list price for Quad is expected to be close to $28,500, which compares to $21,000 for Atripla. Although Atripla is one of the most widely prescribed combinations, use of this 3-in-1 tablet is likely to change as the patent comes to an end for one of its component drugs. When this occurs in 2013, the economic pressure on public health systems is likely to lead to switching to prescribing the individual drugs as separate pills. Unless Gilead reduce their price for Atripla to match the new market, the shift to effective generic alternatives will save the NHS millions of pounds annually. Health care systems in the US are predicting similar changes: with a potential to save close to $900 million if a similar policy to switch to generic versions of efavirenz and 3TC was adopted.
  
  New drugs are commonly marketed at a higher price than existing treatments. This is usually justified by a company to cover their research investment and to recognise qualitative benefits from a demonstrably more effective medicine. As many early HIV medicines come to the end of their patent life, the sustainability of this model is in question, especially for health care systems that are already creaking under the burgeoning role of universal care. A more realistic model – and a long standing activist demand – is for new drugs to be comparable to existing options, and a company should benefit from increased profits based on widespread use of better medicines, not from excessive profits derived from a much smaller number of patients paying exorbitant prices. Health care should not be based on exclusive branding like cars or mobile phone technology.
  
  The strategic decision to price Quad beyond the reach of most people threatens to undermine Gilead’s reputation with doctors, researchers, patients and ultimately shareholders. The easiest way to recoup investment costs for development of a new drug is to price it at a level where it will be widely used. The underlying greed from the current proposed price will make it impossible for activists to argue for patient choice when scarce funding is merely being diverted to pharmaceutical profits. Ultimately, from 27 August onwards, most people in Europe are likely to continue on existing treatments only, and new approvals will become only aspirational care, lanquishing underutilised until their patent expires, just after the announcement of a cure.
  
  The missed opportunity by Gilead to market their newest approval at an affordable price for Western markets casts a dark shadow over their remaining development pipeline which includes several other single and reduced pill formulations, including to the new integrase inhibitor (elvitegravir) and a booster drug called cobicistat (both included in Quad). This short-sighted decision, unless reversed, jeopardises patient care far more seriously than any other drug price launch in the last ten years. (...)

[Puzzle]

Io prenderei più che volentieri una pasticca al giorno, e ne ho già parlato alla mia dott per quando sarà approvato anche in Europa.

Temo dovrai aspettare un po', perché pare che il prezzo esorbitante che Gilead prevede di imporre in Europa possa ritardare di non si sa quanto l'approvazione qui da noi. Vedi Quad approved in US: exorbitant cost likely to block use in Europe.

Grazie, quindi mi sa che morirò con il retrovir

[Jago83]

Allora io non ho capito, e se qualcuno può aiutarmi, per favore:

- perché l'hanno approvato solo per i naive? Vuole dire, per esempio, che chi ha preso Atripla e per qualche motivo il farmaco non dovesse funzionare non può cambiare per QUAD? O ancora, che chi si é stufato degli effetti collaterali di Atripla (questa maledetta sensazione di ubriachezza dopo due ore averla presa) non può cambiare per QUAD?

- Quali sono esattamente gli effetti collaterali di questo farmaco? Non riesco a capirli...

- Una volta ricevuta l'approvazione dalla FDA bisogna aspettare quella europea vero? che solitamente arriva dopo quanto? E quella italiana?

Grazie mille, so che avete le risposte alle mie semplici domande a portata di tastiera!

[cesar78]

- perché l'hanno approvato solo per i naive? Vuole dire, per esempio, che chi ha preso Atripla e per qualche motivo il farmaco non dovesse funzionare non può cambiare per QUAD? O ancora, che chi si é stufato degli effetti collaterali di Atripla (questa maledetta sensazione di ubriachezza dopo due ore averla presa) non può cambiare per QUAD?

Essendo Stribild (QUAD) un farmaco "quad", contenenti più principi attivi, è espressamente studiato per l'utilizzo giornaliero da parte di chi comincia (naive). E' ovviamente l'indicazione ufficiale che da la Gilead. Se l'infettivologo, a conoscenza approfondita della situazione specifica del paziente PRE-TRATTATO, vede che non ci sono interazioni con altir farmaci o reazioni avverse precedenti a qualche composto di Stribild (ma che nome è??) credo che possa decidere di dare lo Stribild anche a chi arriva da precedenti terapie. Ma, ripeto, è una decisione del medico e dipende sempre dalla situazione del paziente: la terapia hiv è personalizzata.

Quali sono esattamente gli effetti collaterali di questo farmaco? Non riesco a capirli...

Alla voce WARNINGS AND PRECAUTIONS del "foglietto illustrativo" c'è un riassunto:
5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis (fegato)
5.2 Patients Coinfected with HIV-1 and HBV (epatite B)
5.3 New Onset or Worsening Renal Impairment (reni)
5.4 Use with Other Antiretroviral Products (interazioni)
5.5 Decreases in Bone Mineral Density (ossa)
5.6 Fat Redistribution (grasso)
5.7 Immune Reconstitution Syndrome (IRIS)
Per i dettagli qui in inglese: http://www.gilead.com/pdf/stribild_pi.pdf
Anche se gli effetti collaterali più grossi possono essere diarrea e nausea. Io resto convinto che qualche problema ai reni questo quad lo dia.

Una volta ricevuta l'approvazione dalla FDA bisogna aspettare quella europea vero? che solitamente arriva dopo quanto? E quella italiana?

Normalmente in Europa qualche mese, ma dipende da molte cose. L'AIFA (agenzia italia per il farmaco) deve sottostare alle approvazioni dell'EMA (Agenzia Europea per i Medicinali) perchè fa parte dell'unione europea.

[Jago83]

Grazie!!!

[skydrake]

Approvato il Quad dall'EMA, col nome di Stribild

Il comitato europeo per i medicinali per uso umano dell'EMA ha dato parere positivo al nuovo farmaco anti HIV che in una sola compressa da somministrarsi once a day associa quattro componenti: emtricitabina, tenofovir, elvitegravir e cobicistat. L'approvazione si riferisce ai pazienti naive al trattamento antioretrovirale. Sviluppato dall’americana Gilead, una volta in commercio il farmaco prenderà il nome di Stribild.

Articolo completo:
http://www.pharmastar.it/index.html?cat=5&id=10720

Il prezzo dovrebbe aggirarsi intorno ai 23.000 euro l'anno:
http://www.quotidianosanita.it/scienza- ... o_id=10579

[skydrake]

L'FDA NON approva l'Elvitegravir e il Cobicistat, che assieme all'Emtricitabina e al Tenoforvir (quindi il Truvava) costituivano i nuovi componenti dello Striblid (Quad):

http://www.pharmastar.it/index.html?cat=4&id=11099

[Boyz84]

L'FDA NON approva l'Elvitegravir e il Cobicistat, che assieme all'Emtricitabina e al Tenoforvir (quindi il Truvava) costituivano i nuovi componenti dello Striblid (Quad):

http://www.pharmastar.it/index.html?cat=4&id=11099

ho letto che la motivazione dovrebbe essere solo burocratica e dunque velocemente reversibile o sbaglio?