- The HCV market is one of the most complex and fascinating environments to be working in at present.
- The disease population is driven by constantly changing drivers, which themselves vary by country, and a deep inspection of the patient flow is the only way to understand the current market and formulate a strategy for the future.
- The same basic patient flow exists in all countries, even though the particulars of the transitions between pools vary widely between the US, Europe, Japan, and the Emerging Markets.
- Incivek and Victrelis are rapidly changing the market landscape, which raises questions about the market environment into which later entrants will emerge, not to mention the immediate future for those products themselves.
- Strategyst Consulting has considerable expertise in epidemiology and forecasting in general, and this market in particular.
Hepatitis C is a viral infection spread by blood-to-blood contact, most commonly through sexual activity, IV drug use, and use of infected blood products. Upon initial infection, a minority of patients experience some form of symptoms, but the majority are asymptomatic. During the acute phase of infection, some patients spontaneously clear the virus, whereas the remaining patients develop long-term chronic infection, defined as active infection that lasts more than six months. In terms of clinical tests, there are two ways to detect HCV:
- Anti-HCV tests probe for the presence of Antibodies to the HCV virus. Antibodies become detectable within one to two years of acute infection, and indicate only that the patient was exposed to the virus at some time in the past, and that an immune response occurred.
- Polymerase Chain Reaction (PCR) tests probe for the presence of HCV-RNA, which becomes detectable within one to two weeks of acute infection, and indicates the presence of active infection.
The key point to recognize is that measurements of Anti-HCV identify the lifetime prevalence of HCV infection, whereas HCV-RNA tests measure the prevalence of current infection. Given the long duration of infection, the fraction of the current HCV-RNA prevalence who have been infected for less than six months, and will eventually self-clear is negligibly small. Self-cure beyond six months is similarly uncommon. Thus, the prevalence of Chronic HCV infection is measured by HCV-RNA positivity.
The natural history of untreated Chronic HCV is typically marked by an asymptomatic period for the first few decades, with gradual development of Fibrosis, leading to Cirrhosis, and consequent increased risk of Hepatocellular Carcinoma (HCC). Mortality rates are higher than the general population prior to the onset of liver-related outcomes, principally due to lifestyle factors that tend to co-occur in the at-risk population (drug use, incarceration, for example). The goal of treatment is to achieve Sustained Viral Response (SVR), defined as a reduction of HCV-RNA to undetectable levels lasting at least six months after completion of treatment. Such patients are usually considered cured, although there is a 1-2% risk of subsequent relapse.
Interferon (IFN) was the backbone of early treatment for HCV between its formal identification in the late 1980s (prior to which it was known only as Non-A/Non-B Hepatitis), until the availability of Pegylated forms of Interferon (Peg-Intron and Pegasys) in the early 2000s. Until recently, Pegylated Interferon (Peg-IFN) in combination with Ribavirin (RBV) was the Standard-of-Care in the treatment of HCV.
IFN achieves SVR in around 35% of treated patients, with Peg-IFN+RBV increasing the SVR to around 50% overall (different viral genotypes respond differently). It’s also important to understand that the SVR rate for treatment depends on the patient’s age – younger patients respond better than older patients. This becomes important when we consider the demographics that emerge from the patient flow.
For the past 20 years or so, limited treatment options, the best of which is characterized by inconvenient dosing, frequently intolerable side effects, and near 50:50 odds of success have led, unsurprisingly, to fairly low treatment rates, and a lack of enthusiasm among the medical community for proactively screening for infection in all but the highest risk groups (chiefly IV drug users and prison inmates). The overall diagnosis rate is fairly low for a disease with such serious long-term complications, with the slow rate of progression leading to a general lack of urgency among physicians in seeking out these patients.
This is the environment into which the latest wave of small molecule antivirals is entering. Early entrants (Vertex’s Incivek, and Merck’s Victrelis, both Protease Inhibitors) are already available in the US, Europe and Japan, with Incivek being the market leader, posting impressive early sales of close to $1 Billion (net) in its launch year. In addition to these products, there is a robust pipeline of products in clinical trials, comprising additional Protease Inhibitors, as well as Polymerase Inhibitors and a number of other modes of action.
All currently-approved regimens involve Peg-IFN and RBV, but work is being done towards Interferon-Free regimens which offer the promise of higher SVR rates, and more benign tolerability profiles.
HCV is a relatively simple marketplace, but has quite complex population dynamics. A conventional prevalence-based model is simply inadequate to the task of tracking the true opportunity for products entering the market. For this reason, we have looked at the patient flow within the HCV market, as a means to capture the drivers that affect the patient pools. Key points in these models include:
- The incidence of HCV has been variable over time, and varies substantially between countries. In the US, for example, there was a large incidence spike during the 1970s, corresponding to infected blood products used to treat injures soldiers in the Vietnam War. There was another large spike around 1990, attributable to the popularity of intravenous illegal drugs. Both spikes tended to infect people in their 20s and 30s, leading to a demographic bubble in those cohorts. Subsequent to those spikes, incidence has dropped substantially. In other countries, however, the incidence is higher, and the prevalent pool is not declining the way it is in the US. In emerging markets, for example, HCV infection is still commonplace.
- The demographics of this bubble of newly infected patients have given rise to a wave of aging patients, with the mean age of the HCV population drifting upwards every year.
- Mortality rates are increasing as the mean age increases, due partially to the normal causes of death in the elderly, as well as a patient population who are increasingly encountering the sequelae of their disease, and dying of cirrhosis and HCC-related complications.
- It is by no means given that a patient will initiate treatment promptly upon diagnosis. There is frequently a gap between diagnosis and treatment, and many patients have died, never having been treated.
- Further to this last point, dissatisfaction with the outlook for conventional treatment (intolerable side-effects and mediocre odds of success), combined with growing awareness of promising new treatments has led to a phenomenon variously referred to as ‘treatment deferral’ or ‘patient warehousing’, whereby specialists are deliberately withholding treatment from their patients until the new products become available.
- Upon treatment, there is a portion of patients who drop out very quickly due to side effects and adverse events. These patients are, at present, ineligible for treatment, and form a steadily growing pool of Interferon Intolerant patients, strong candidates for IFN-Free regimes. Patients treated successfully are considered cured, and leave the prevalent pool altogether. Patients who tolerate and complete their course of therapy, yet fail to achieve SVR move on to another pool of Treatment Failures. There is a small fraction of these patients who choose to undergo retreatment with a similar regimen (perhaps substituting Peg-Intron for Pegasys or vice versa), but the outlook for these patients is not hopeful, having already failed once. This pool of Treatment Failures is another source of patients for new small-molecule antivirals.
So, in simple terms, the patient flow tells us that there’s a pool of diagnosed, never-treated Naïve patients, a pool of Interferon-Intolerant patients who might be described as quasi-Naïve, and a pool of Treatment Failures. All this occurs against a background of shifting demographics as the population ages at a rate defined by the age profile of the incident population, treatment rates (which determine the cured population), and increasing mortality rates. When we combine this with the current market outlook, a number of pertinent questions arise:
- Given the demographics of the prevalent RNA-positive HCV pool, the relatively low rate of new infections, and historically low diagnosis rates, what evolution do we expect for the Treatment-Naive market, and how much of it will be left by the time the next new antivirals launch?
- How does the prevalence vary between the US, Europe, and Emerging Markets?
- Peg-Interferon sales declined over recent years. Was that a reflection of patient pool depletion or a lack of satisfaction with the then-current standard of care?
- To what extent is the early success of Incivek and Victrelis a function of previous patient warehousing, how long will that effect last, and what will the market look like after those patients have been treated?
- If efforts to increase surveillance are successful, how many newly-diagnosed patients can we expect, and what impact will they have on the market for Naïve patients?
- How will varying efficacy rates among the therapy choices affect the size of the pool of Treatment Failures coming from the Treatment-Naive pool?
- What is the distribution of viral genotypes within the Naïve population, and given the different levels of efficacy within these genotypes, how does that distribution differ in the Treatment Failure pool?
- How large is the opportunity for IFN-Free regimens in Interferon-Intolerant patients?
- How will the market react to Interferon-Free regimens in patients who tolerate Peg-IFN?
- Given the variation in efficacy as a function of patient age, how does the aging of the HCV prevalent pool affect real-world future SVR rates, relative to the values reported in clinical trials?
- What is the anticipated pharmacoeconomic impact of curing HCV today on HCC incidence and costs in the future, and when will they be realized? Does that impact justify coverage for expensive triple- and quadruple-product regimens
It is possible to forecast both the epidemiology and commercial environment together, so that changes in market behavior are reflected in the subsequent patient pool opportunity, and this is the approach we have taken in looking at this market in the past. To learn more about how we can help you refine your understanding of this complex and fascinating market place, please contact the author directly.