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HIV Indication Report - Update
March 13, 2007
CCR5 antagonists
Maraviroc is set to be the first CCR5 inhibitor to come to market. CCR5 inhibitors are a new class of drugs that inhibit viral entry into host cells by preventing viral binding to the CCR5 coreceptor. While CD4 is the primary host cell receptor for viral entry, binding to a coreceptor is necessary for viral entry; the two main coreceptors used by HIV are CCR5 and CXCR4. HIV typically utilizes the CCR5 coreceptor in early disease (called M-tropic or CCR5 tropic virus) while CXCR4 (CXCR4 tropic) is often associated with more advanced and aggressive disease. HIV can also use a mixture of these coreceptors and this is referred to as dual or mixed tropic. Based on published literature, 81-88% of treatment-naïve patients are R5 tropic compared to 67-78% of treatment-experienced and 49-50% of heavily treatment-experienced patients.
Pfizer filed an NDA for Maraviroc in January 2007 which received a priority review. The FDA is expected to make a decision in or by June 2007 following an advisory meeting in April 2007. Approval is based on two phase II/III studies called MOTIVATE 1 and 2 in highly treatment-experienced patients. While both studies are 48 week trials, accelerated approval is likely to be granted on interim 24-week data.
The 24-week data that was presented at CROI was the first real look into the efficacy and safety of Maraviroc. The data showed that in patients with CCR5 tropic disease, the addition of Maraviroc to optimized background therapy (OBT) resulted in better viral control than OBT alone. OBT can comprise three to six approved HIV drugs. The data were remarkably consistent between the two MOTIVATE studies with results showing that Maraviroc reduced viral load by almost 2 log10 (range 1.82 to 1.97 log10 copies/ml) compared to approximately a 1 log10 reduction in the control arm (range 0.93 to 1.03 log10). Approximately twice as many patients on the Maraviroc arms achieved an undetectable viral load compared to OBT alone when measured by the old limit of detection (<400 copies/ml: 55-61% compared to 23-31%) and by the new ultrasensitive limit of detection (<50 copies/ml: 41-48% compared to 21-25%). In addition, patients receiving Maraviroc had superior increases in CD4 T cell counts compared to control patients. Interestingly, the results between once-daily and twice-daily Maraviroc administration were similar, suggesting that once-daily Maraviroc is sufficient for efficacy which should help with patient adherence to the new drug regimen.
These results clearly indicate that the addition of Maraviroc to OBT improved virologic control in patients with CCR5 tropic disease. These results are impressive given the heavily pretreated nature of these patients. Importantly, no cases of hepatotoxicity or lymphomas or other malignancies were seen in these studies. This is of great importance since other CCR5 inhibitors have been plagued by these issues: GSK's Aplaviroc was suspended due to hepatotoxicity while development of Schering's Vicriviroc has been hampered due, in part, to 5 cases of malignancies seen in a study in treatment experienced patients. While malignancies were likely to be specific to Vicriviroc, hepatoxicity was a real concern for Maraviroc since a case of liver toxicity leading to liver failure was seen in a treatment-naïve patient taking Maraviroc. Although the liver failure was most likely due to concomitant drugs the patient was taking, a causal role for Maraviroc could not be ruled out at the time. However, the lack of hepatoxicity in the MOTIVATE studies in over 800 patients given Maraviroc for over 24 weeks helps provide meaningful evidence that Maraviroc does not cause liver toxicity.
The impressive efficacy data, coupled with the lack of liver toxicity and malignancies, should lead to an accelerated FDA approval in June given the vast need for new HIV drugs for patients with drug resistant disease. However, Maraviroc's use is likely to be limited to patients with CCR5 tropic disease since an earlier study showed that the drug has little benefit in patients with dual tropic disease or CXCR4 tropic disease. While Maraviroc can potentially be used in treatment-naïve patients, we believe that concerns regarding coreceptor switching is likely to keep adoption in these patients to a minimum. In the MOTIVATE studies, 31 patients in the once-daily Maraviroc groups (out of 414 patients) and 32 patients (out of 426) in the twice-daily Maraviroc groups had their CCR5 tropic virus switch to become CXCR4 tropic or dual tropic. This equates to 7.5% of patients taking Maraviroc experiencing coreceptor switching and this switching led to a muted response to Maraviroc or loss of an earlier response. Given the association of more aggressive disease when HIV utilizes the CXCR4 coreceptor, we believe these results will ensure that Maraviroc only be used in patients needing a new drug to add to their failing regimens.
HIV integrase inhibitors
Two integrase inhibitors are currently in mid to late stage clinical development with Merck's Isentress being the furthest along. HIV integrase is a novel target that is designed to prevent the incorporation of viral DNA into host cell DNA. After HIV binds to host immune cells, it releases its contents (viral RNA and the enzymes reverse transriptase and integrase) into host cells. Once reverse transcriptase converts the viral RNA into DNA, the enzyme integrase incorporates the viral DNA into the cell's DNA. Therefore, integrase inhibitors block a major pathway in the HIV infection cycle and target an enzyme not found in human cells (which may potentially reduce side effects).
Isentress is currently in two phase III studies in treatment-experienced patients. Interim 16-week results from these two studies, BENCHMRK-1 and -2, were presented at CROI. Similar to Maraviroc, twice as many patients on Isentress achieved an undetectable viral load when measured by the ultrasensitive limit (61-62% of patients given Isentress compared to 33-36% of patients given OBT alone). When measured by the old standard of 400 copies/ml, 77% of Isentress patients had undetectable viral load compared to 41-43% of control patients. Isentress also significantly improved CD4 T cell counts relative to control. As with the Maraviroc MOTIVATE studies, these two Isentress studies were remarkably consistent and as expected, Isentress was well tolerated with adverse effects being similar between the Isentress and the control groups.
Elvitegravir (GS 9137; Gilead)
Elvitegravir, formerly known as GS 9137, is currently in phase II studies. Similar to Isentress, the drug can be administered twice-daily, however this dosing can be reduced to once-a-day with ritonavir (Norvir; Abbott) boosting. Ritonavir-boosting is used with some protease inhibitors to extend their half-lives and in the case of Elvitegravir, it increases drug level by 20-fold to allow for once-daily dosing.
Interim data from the phase II study were presented at CROI. This study is a 48 week non-inferiority study (to comparable protease inhibitors) designed to evaluate 3 different doses (20, 50, and 125 mg) of Elvitegravir, however the lowest dose cohort was stopped in October 2006 after the study's Data Safety Monitoring Board (DSMB) recommended closure due to lack of efficacy.
The study's primary endpoint is viral load at 24 weeks, which was presented at the recent CROI meeting. The results showed that regimens containing 50 mg or 125 mg of Elvitegravir were as efficacious, if not more so, than regimens containing comparator protease inhibitors. At 24 weeks, 27% of patients achieved undetectable viral load (<50 copies/ml) in the control arm, compared to 32% and 36% in the 50 mg and 125 mg Elvitegravir. These results clearly demonstrate that Elvitegravir was non-inferior to an optimized background therapy and the responses to Elvitegravir were durable when it was included in a regimen that contained at least one other active drug.
Based on the number of patients achieving an undetectable viral load at week 16, it would appear that Isentress is more potent than Elvitegravir. However, the design of the Elvitegravir study places the drug at a significant disadvantage. In the Isentress studies (BENCHMRK-1 and -2), Isentress was added on top of OBT. In the Elvitegravir study, patients received Elvitegravir in place of protease inhibitors in the first 8 weeks of the study (after which patients were allowed to add one of two protease inhibitors to their regimen). Results from this study found that Elvitegravir reduced viral load by more than 2 log10 initially but this response was lost over time if patients did not have another active drug in their regimen. In patients with an additional active drug in their regimen, the response was more durable and was maintained at 24 weeks. Thus, the number of patients achieving an undetectable viral load in the Elvitegravir arms at week 16 and week 24 may be inadvertently low because of the lack of an OBT. Therefore, while initial glimpses appear to suggest Isentress to be more potent, we believe that Elvitegravir has demonstrated potent efficacy and is likely to demonstrate better efficacy when added to an OBT in a phase III study.
MARKET OUTLOOK
The data seen with Maraviroc and Isentress are impressive. These two drugs are the first new oral agents in over a decade to show a clinical benefit in advanced HIV patients and since they work via different mechanisms of action, they provide a much needed boost to the HIV armamentarium. It should be noted that the 60-80% of patients achieving the 400 copies/ml limit with Maraviroc and Isentress is as high as that seen in treatment-naïve patients in the early days of HAART therapy. Given the vast need for new anti-HIV drugs, particularly for patients already resistant to the three main drug classes (NRTI, NNRTI and PI), we expect few hurdles for the approval of these two drugs.
Maraviroc will be the first to come to market, with approval expected in June 2007 following an advisory committee meeting on April 24, 2007. While Maraviroc has shown remarkable efficacy, given the numerous setbacks with CCR5 inhibitors (liver toxicity, virologic breakthroughs and malignancies) and the potential for coreceptor switching, we are not surprised that an FDA advisory meeting was necessary. While we are still concerned by the approximately 7.5% of patients showing coreceptor switching in the MOTIVATE studies, we believe that there is sufficient need for this drug for it to receive approval. While CCR5 tropic virus is seen more frequently in early HIV disease, we expect the drug to be used primarily in heavily treatment-experienced patients.
Isentress should also attain FDA approval without hurdles. An NDA is expected in the second quarter of 2007 and we expect a priority review for the drug which means Isentress could be on the market by the end of 2007 or early 2008. While Gilead’s Elvitegravir is further behind in development, we anticipate a relatively smooth clinical development (given the lack of toxicity signals with Isentress) and an FDA approval in 2009.
Given the immense need for new anti-HIV agents, we expect all three drugs to become widely adopted in treatment-experienced patients. We now see a wide adoption of Maraviroc in these patients although we expect the drug to only be used in patients with CCR5 tropic disease (which represents approximately 50% of heavily pretreated patients) and not dual tropic or CXCR4 tropic patients. We also expect a big uptake of Isentress in treatment experienced patients. While Isentress appears to work better in patients with lower viral loads and higher CD4 counts (which suggests it should be tried first before Maraviroc), the association of CXCR4 tropism in more advanced patients means that Maraviroc needs to be utilized before the disease become too advanced. Therefore, since both drugs have reasons for use earlier on, they are likely to split the market. While we see both drugs being competitive with a wide adoption in treatment-experienced patients, we project a slightly stronger uptake for Isentress than Maraviroc since the drug is not limited to a specific patient subgroup. We also expect Elvitegravir to do well, particularly since the drug is dosed once-daily (compared to Isentress being given twice-a-day). However, Elvitegravir is likely to suffer slightly because of the second-to-market disadvantage although we expect this disadvantage to be small since there is a continual need for newer agents even in the same drug class due to the high mutation (and thus resistance development) rate of HIV.
It is not known if the two new drug classes can be combined. Although studies are not yet available, pharmacokinetically, it appears possible that CCR5 inhibitors can be combined with integrase inhibitors. However, these studies will need to be carried out and we expect these drugs to be used in separate regimens (in a sequential manner) initially so that patients will have another viable option once they develop resistance to the first agent.
There are also questions as to resistance development. Data on Maraviroc is still scarce and it is not known whether resistance to Maraviroc will lead to resistance to other CCR5 inhibitors (such as Vicriviroc). In the case of integrase inhibitors, there appears to be two separate mutation pathways for Isentress and Elvitegravir. Data for Isentress have shown that N155H and Q148K/R/H mutations lead to resistance to the drug. Two different mutations have been shown to result in Elvitegravir resistance: T661 and E92Q. Interestingly, in a separate presentation at CROI, it was noted that while T661 mutations resulted in resistance to Elvitegravir but not Isentress, E92Q mutations conferred resistance to both drugs, thus indicating that cross-resistance is a real possibility. However, all mutations to integrase inhibitors appear to be fully susceptible to other antiretroviral drug classes. Limited data also suggests that resistance to integrase inhibitors do not occur as quickly as for the NNRTI class of drugs, but is likely to be quicker than with protease inhibitors. Therefore, due to Elvitegravir’s second to market disadvantage and the possibility of cross-resistance, while we still expect a strong uptake of the drug, we project it to be less than for Isentress.
REVENUE MODEL UPDATES
Fundamental Changes
We have updated two fundamental aspects of our HIV model in order to stay up to date with the ongoing changes in the HIV market.
In September 2006, the CDC revised its recommendation for HIV testing with the goal of increasing the rate of early diagnosis. Specifically, they now recommend that HIV testing “be a part of routine clinical care in all health-care settings”, which includes hospitals, urgent-care centers, various clinics, and primary care settings. These changes come as a result of the changing demographics of the HIV epidemic. Over the last decade, the number of HIV cases among members of certain racial/ethnic minority populations and persons exposed through heterosexual contact has increased and therefore, new recommendations are needed.
Based on the likelihood of an increase of early diagnosis due to the new CDC recommendations, we have increased our estimated growth rate of the percent of patients who are aware they are infected with the HIV virus. Current studies indicate that only 75% of HIV positive patients are aware they are infected. We estimate this percentage will increase to approximately 85% from the current level of 75% over the next 10 years.
The second change we have made involves our assumption of how many patients are in each line of therapy. We currently assume 50% of HIV patients are 1st line, 30% are 2nd line, and 20% are 3rd line and beyond. Due to the increased time of survival over the last decade and the high likelihood that novel drugs (CCR5 antagonists, integrase inhibitors), will be available in the near future, we are growing the share of the 2nd and 3rd line patients while decreasing the percent of 1st line patients. By 2017 we anticipate approximately 42% of patients will be 1st line, 34% 2nd line, and 24% 3rd line and beyond.
Drug Revenue Model Updates
We previously had low expectations for Maraviroc given the toxicity issues seen with other CCR5 inhibitors and the single case of liver failure with Maraviroc. Given the efficacy data from the MOTIVATE studies and the lack of liver toxicity or malignancies, we now expect the drug to become widely adopted in treatment-experienced patients. We have increased our peak market share estimate for subsequent line patients (3rd Line and beyond) to 22.5% from a previous level of 6%. Additionally, we now include Maraviroc in the 2nd line setting with 5% peak market share. Peak U.S. and worldwide revenue is modeled to reach $426 and $637 million in 2014.
Our market share estimate for Merck’s integrase inhibitor, Isentress has also increased from our last HIV update. We expect a slightly higher adoption of Isentress compared to Maraviroc since more patients are eligible for Isentress (Maraviroc is limited to CCR5 tropic patients). We continue our optimistic stance on Isentress with subsequent line peak market share increasing to 27.5% from 20%. Similar to Maraviroc, we also include Isentress in the 2nd Line setting with 5% peak share. Peak U.S. and worldwide revenue is expected at $520 and $822 million.
We remain positive on Gilead’s integrase inhibitor Elvitegravir (GS 9137) and have increased our subsequent line peak market share estimate to 22.5% from 15% after seeing the 24-week data that was presented at the CROI conference. We have the market share slightly below Merck’s Isentress since Isentress will enjoy first-to-market advantage and Elvitegravir may be disadvantaged by cross-resistance (although Elvitegravir may be preferred by some due to its less frequent dosing). We project a 2nd line peak market share of at 4%. U.S. and worldwide peak revenue is expected at $452 and $684 million.
Our cautious view of Panacos’ maturation inhibitor Bevirimat remains unchanged since our last HIV update and coverage initiation of the company. As previously discussed, we continue to favor the integrase inhibitors over Bevirimat since Bevirimat has demonstrated less potency (at doses tested thus far) and currently do not expect the drug to gain significant market share (assuming approval) relative to other novel antiretroviral drugs (pending data on higher doses of Bevirimat). Panacos recently announced that they will continue the Phase IIb dose-escalation study using the liquid dose formulation of Bevirimat. Therefore, we will closely monitor results from this phase IIb study and will provide updates as needed. For the time being, peak market share is unchanged and estimated at 10% of subsequent line patients. U.S. and worldwide peak revenue is projected at $229 and $357 million.
Gilead and Bristol Myers saw a rapid uptake of Atripla following the U.S. launch in July of last year. Sales for 2006 reached $206 million and will continue at a fast pace this year with approval in Europe expected during the second half of 2007. According to Gilead, prescription data indicates that the launch of Atripla surpasses that of Truvada, which at the time was the number one antiretroviral launch of all new HIV medications.
While a good portion of the Atripla growth was the result of patients switching from Truvada + Sustiva, some of the sales came at the expense of Combivir. Gilead stated on its Q4 conference call that patients shifting from Combivir accounted for 15% of the switches to Atripla during the first three months after the launch. We anticipate a continual, gradual decline in Combivir sales going forward given the success of Truvada, and now Atripla. Our projected sales for Atripla reach $1.47 billion in the U.S. and $2.21 billion worldwide by 2011.
For our disclosures, please read the BioMedTracker Research Standards.