The Big PicturePublication Exclusive

Looking Back, Looking Ahead at Treatment Developments

Since early in 2015, this has been a very eventful year for hepatitis C therapeutics and we can summarize our experiences over the last year much like Clint Eastwood’s spaghetti Western: The Good, The Bad and The Ugly.

The Good

The good is fairly obvious. Several new drugs that we discussed as being in the pipeline last year were approved in the United States in 2015, with newer and even more potent drugs taking their places in the wings.

Leading the approval charge was daclatasvir (Daklinza, Bristol-Myers Squibb), approved in the summer. Daclatasvir is available now for treatment, most importantly for those with genotype 3 disease, but it’s also available for patients with genotypes 1 and 2. AbbVie launched a modified version of its approved drugs with the release of a specifically packaged version of paritaprevir/ritonavir/ombitasvir (Technivie) for genotype 4 infection.

The approval of daclatasvir also allowed for the ongoing process of updating the AASLD/IDSA guidelines to shine.

Daclatasvir received approval on July 24, 2015. The committee had a formal update to the guidelines just weeks later, recommending an all-oral regimen consisting of sofosbuvir (Sovaldi, Gilead Sciences) and daclatasvir for patients with genotype 3 HCV.

Michael S. Saag

A second update to the guidelines in August brought cost-effectiveness insight to providers of HCV treatment. While this insight does not affect the treatment recommendations given by the committee, it is important that we, as providers, are aware of where we stand on cost effectiveness as these treatments continue to push monetary boundaries.

Therefore, in 2015, we exemplified once again how these guidelines truly exist as a living, breathing document, changing as quickly as our treatment landscape.

In the pipeline, the grazoprevir/elbasvir (MK-5172, MK-8742; Merck) combination both lost and received breakthrough designation from the FDA. After an initial notification that the designation would be rescinded, the FDA granted breakthrough designation due to the research seen with this combination in patients with HCV and end stage renal disease, accelerating its pathway to approval expected early in 2016.

Studies were reported at the International Liver Congress and The Liver Meeting, demonstrating high levels of efficacy in multiple genotypes and multiple populations of patients. Yet, perhaps the most promising area of use for this compound is its safety and efficacy in patients with more advanced renal disease. If approved for this indication, this will definitely be a niche for these products and a service to patients who have previously been understudied and undertreated.

Another area of good news is continued development of new drug products by multiple companies, with a trend heading toward pangenotypic drugs given in once-daily combinations, and we expect to see more of that in 2016.

The Bad

The bad of 2015 emerged mainly as drug-drug interactions and toxicities seen in daily practice once newly approved drugs were given to many of our patients.

The first major warning came for drug-drug interactions with amiodarone and sofosbuvir-based combinations. This interaction, which led to a label change mandated by the FDA, can lead to potentially fatal arrhythmias. Vigilance needs to be exercised when using these new direct-acting antiviral agents with several other drugs, but in particular amiodarone.

In addition to drug-drug interactions, we saw unexpected toxicities with certain medications. An example of this was paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD; Viekira Pak, AbbVie) and ombitasvir/paritaprevir/ritonavir combination medications demonstrating more liver toxicity in those with compensated cirrhosis than was originally anticipated. These drugs are contraindicated among those with Child-Turcotte-Pugh (CTP) class B or C disease; however, the observation that some patients with CTP class A disease decompensated within the first 4 weeks of therapy created an FDA warning letter and a change in the AASLD/IDSA guidelines that more frequent monitoring of CTP A patients should be implemented to ensure that decompensation is not occurring. The guidelines also suggest discussion of the potential of liver decompensation with CTP class A patients prior to initiation of PrOD regimens.

These warnings underscore the need for vigilance of all providers to watch for unanticipated drug-drug interactions or toxicities as a natural consequence of rapid drug approval. New drugs enter the market early with only several thousand patients treated at the approved dose and duration. It’s inevitable that certain drug toxicities will emerge that were not seen in the relatively small pivotal trials that led to the drug’s approval.

The Ugly

The ugly of 2015 is observed in any provider’s practice on any given day.

Many patients arrive for their visits, undergo an assessment and the provider decides to treat them for their hepatitis C and cure them of their viral infection. Unfortunately, third party payers often refuse to cover the cost of DAA therapy for patients with F0 to F2 fibrosis and no other indication for therapy.

This translates into frustration for both the providers and the patients. The patients continue to show up in clinics for their evaluation only to be told, “Well, we intended to treat you, but we can’t get approval from your insurance company.”

The concern I have is the accumulation of patients who now are sent into “orbit” waiting for their prescription approvals. They keep returning to their clinic every 4 to 6 months for follow-up, only to be told the same thing again and again.

Images of Sisyphus and his struggle to continually roll a boulder up the hill only to have it fall down again come to mind as I think about resending appeals to the insurance companies. Until this cycle is broken, frustration will remain in the practices of providers who care for patients infected with HCV.

The Future

In some ways, 2016 should be more of the same in the treatment realm, if not a little better in terms of new drugs being approved and therapeutic options increasing.

With both the grazoprevir/elbasvir and sofosbuvir/velpatasvir (GS-5816, Gilead Sciences) combinations likely to receive FDA approvals in the first quarter and half of 2016, respectively, we likely will see our first truly pangenotypic regimens in practice.

As Ira M. Jacobson, MD, my co-chief medical editor, mentioned in his Take Home from the Liver Meeting last month, a hot topic with these regimens is resistance-associated variants (RAVs) and their impact on treatment. In 2016, one thing we should be watching for is the emergence of drug resistance assays and their more routine use in the treatment of HCV. There is speculation that the approval of grazoprevir/elbasvir may include a requirement to test for RAVs to determine the best treatment regimen (including ribavirin or not) as well as duration of therapy.

With more FDA approvals of drugs from competing companies, my hope is that some degree of price competition will emerge and lead to lower costs of treatment, thereby breaking the backlog of denial letters from the insurance companies. Unfortunately, I’m a little disheartened as I think about the absence of an apparent free market in the world of pharmaceutical therapeutics.

It will be interesting to watch what happens on Capitol Hill in Washington as congressional committees on pharmaceutical drug pricing are formed. I personally doubt there will be anything that comes out of these committees other than of a lot of press releases and published reports. The report that came out from the FDA on Nov. 4, described in detail how pricing for Gilead’s products were developed, but on reading the document carefully, there were no actionable items proposed.

Until there’s either genuine increased competition or prices come down to something that the insurance companies can afford, then, in many ways, 2016 will be a copy and paste of 2015.

Disclosure: Saag reports receiving research grants, paid to his institution, from AbbVie, Bristol-Myers Squibb, Gilead Sciences Inc., Janssen Therapeutics, Inc., Merck & Co. Inc., and ViiV Healthcare.

Since early in 2015, this has been a very eventful year for hepatitis C therapeutics and we can summarize our experiences over the last year much like Clint Eastwood’s spaghetti Western: The Good, The Bad and The Ugly.

The Good

The good is fairly obvious. Several new drugs that we discussed as being in the pipeline last year were approved in the United States in 2015, with newer and even more potent drugs taking their places in the wings.

Leading the approval charge was daclatasvir (Daklinza, Bristol-Myers Squibb), approved in the summer. Daclatasvir is available now for treatment, most importantly for those with genotype 3 disease, but it’s also available for patients with genotypes 1 and 2. AbbVie launched a modified version of its approved drugs with the release of a specifically packaged version of paritaprevir/ritonavir/ombitasvir (Technivie) for genotype 4 infection.

The approval of daclatasvir also allowed for the ongoing process of updating the AASLD/IDSA guidelines to shine.

Daclatasvir received approval on July 24, 2015. The committee had a formal update to the guidelines just weeks later, recommending an all-oral regimen consisting of sofosbuvir (Sovaldi, Gilead Sciences) and daclatasvir for patients with genotype 3 HCV.

Michael S. Saag

A second update to the guidelines in August brought cost-effectiveness insight to providers of HCV treatment. While this insight does not affect the treatment recommendations given by the committee, it is important that we, as providers, are aware of where we stand on cost effectiveness as these treatments continue to push monetary boundaries.

Therefore, in 2015, we exemplified once again how these guidelines truly exist as a living, breathing document, changing as quickly as our treatment landscape.

In the pipeline, the grazoprevir/elbasvir (MK-5172, MK-8742; Merck) combination both lost and received breakthrough designation from the FDA. After an initial notification that the designation would be rescinded, the FDA granted breakthrough designation due to the research seen with this combination in patients with HCV and end stage renal disease, accelerating its pathway to approval expected early in 2016.

Studies were reported at the International Liver Congress and The Liver Meeting, demonstrating high levels of efficacy in multiple genotypes and multiple populations of patients. Yet, perhaps the most promising area of use for this compound is its safety and efficacy in patients with more advanced renal disease. If approved for this indication, this will definitely be a niche for these products and a service to patients who have previously been understudied and undertreated.

Another area of good news is continued development of new drug products by multiple companies, with a trend heading toward pangenotypic drugs given in once-daily combinations, and we expect to see more of that in 2016.

The Bad

The bad of 2015 emerged mainly as drug-drug interactions and toxicities seen in daily practice once newly approved drugs were given to many of our patients.

The first major warning came for drug-drug interactions with amiodarone and sofosbuvir-based combinations. This interaction, which led to a label change mandated by the FDA, can lead to potentially fatal arrhythmias. Vigilance needs to be exercised when using these new direct-acting antiviral agents with several other drugs, but in particular amiodarone.

In addition to drug-drug interactions, we saw unexpected toxicities with certain medications. An example of this was paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD; Viekira Pak, AbbVie) and ombitasvir/paritaprevir/ritonavir combination medications demonstrating more liver toxicity in those with compensated cirrhosis than was originally anticipated. These drugs are contraindicated among those with Child-Turcotte-Pugh (CTP) class B or C disease; however, the observation that some patients with CTP class A disease decompensated within the first 4 weeks of therapy created an FDA warning letter and a change in the AASLD/IDSA guidelines that more frequent monitoring of CTP A patients should be implemented to ensure that decompensation is not occurring. The guidelines also suggest discussion of the potential of liver decompensation with CTP class A patients prior to initiation of PrOD regimens.

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These warnings underscore the need for vigilance of all providers to watch for unanticipated drug-drug interactions or toxicities as a natural consequence of rapid drug approval. New drugs enter the market early with only several thousand patients treated at the approved dose and duration. It’s inevitable that certain drug toxicities will emerge that were not seen in the relatively small pivotal trials that led to the drug’s approval.

The Ugly

The ugly of 2015 is observed in any provider’s practice on any given day.

Many patients arrive for their visits, undergo an assessment and the provider decides to treat them for their hepatitis C and cure them of their viral infection. Unfortunately, third party payers often refuse to cover the cost of DAA therapy for patients with F0 to F2 fibrosis and no other indication for therapy.

This translates into frustration for both the providers and the patients. The patients continue to show up in clinics for their evaluation only to be told, “Well, we intended to treat you, but we can’t get approval from your insurance company.”

The concern I have is the accumulation of patients who now are sent into “orbit” waiting for their prescription approvals. They keep returning to their clinic every 4 to 6 months for follow-up, only to be told the same thing again and again.

Images of Sisyphus and his struggle to continually roll a boulder up the hill only to have it fall down again come to mind as I think about resending appeals to the insurance companies. Until this cycle is broken, frustration will remain in the practices of providers who care for patients infected with HCV.

The Future

In some ways, 2016 should be more of the same in the treatment realm, if not a little better in terms of new drugs being approved and therapeutic options increasing.

With both the grazoprevir/elbasvir and sofosbuvir/velpatasvir (GS-5816, Gilead Sciences) combinations likely to receive FDA approvals in the first quarter and half of 2016, respectively, we likely will see our first truly pangenotypic regimens in practice.

As Ira M. Jacobson, MD, my co-chief medical editor, mentioned in his Take Home from the Liver Meeting last month, a hot topic with these regimens is resistance-associated variants (RAVs) and their impact on treatment. In 2016, one thing we should be watching for is the emergence of drug resistance assays and their more routine use in the treatment of HCV. There is speculation that the approval of grazoprevir/elbasvir may include a requirement to test for RAVs to determine the best treatment regimen (including ribavirin or not) as well as duration of therapy.

With more FDA approvals of drugs from competing companies, my hope is that some degree of price competition will emerge and lead to lower costs of treatment, thereby breaking the backlog of denial letters from the insurance companies. Unfortunately, I’m a little disheartened as I think about the absence of an apparent free market in the world of pharmaceutical therapeutics.

It will be interesting to watch what happens on Capitol Hill in Washington as congressional committees on pharmaceutical drug pricing are formed. I personally doubt there will be anything that comes out of these committees other than of a lot of press releases and published reports. The report that came out from the FDA on Nov. 4, described in detail how pricing for Gilead’s products were developed, but on reading the document carefully, there were no actionable items proposed.

Until there’s either genuine increased competition or prices come down to something that the insurance companies can afford, then, in many ways, 2016 will be a copy and paste of 2015.

Disclosure: Saag reports receiving research grants, paid to his institution, from AbbVie, Bristol-Myers Squibb, Gilead Sciences Inc., Janssen Therapeutics, Inc., Merck & Co. Inc., and ViiV Healthcare.