Fall out from Merck's announcement that vicriviroc has failed in phase III treatment experienced trials

In 2008, antiretroviral sales across the seven major markets totaled $10.7 billion, growing at a CAGR of 12.8% between 2005 and 2008. This expansion is expected to slow down. Despite drivers such as new product launches, earlier treatment initiation, decreasing mortality and an increase in HIV prevalence, a series of patent expiries will impact branded sales from 2011. [See Forecast Insight: HIV - Cross-class fixed dose combinations drive continued growth]

The dynamic nature of the HIV market has been further evidenced by Merck's announcement last week that it will not, for the moment, be submitting an NDA for vicriviroc in treatment-experienced HIV-infected patients. This news came with the disclosure that two Phase III studies in this patient population failed to meet their primary efficacy endpoint.

Results from these studies will be presented at CROI in February.

Cowen and Co had already expected vicriviroc to achieve modest sales, $75 million in 2012, growing to $150 million in 2015. These figures will have to be revised.

Patients were recruited to the two Phase III trials, VICTOR-E3 and VICTOR-E4, only if they had documented resistance to at least two antiretroviral drug classes. Patients were treated with an optimized background regimen (ritonavir boosted protease inhibitor plus at least two active drugs) with or without vicriviroc.

Even with resistance to at least two antiretroviral drug classes, efficacy rates of 90% can nowadays be achieved with antivirals such as Merck's Isentress (raltegravir) or Tibotec/Johnson & Johnson's Prezista (darunavir) and Intelence (etravirine).

This supports Merck's explanation that the trials failed because many patients enrolled had three or more active drugs in their optimized background therapy regimen. Unsurprisingly therefore, this would leave little room for newer agents such as vicriviroc to show any additional benefits. While plausable we can't help but ask why this potential problem wasn't foreseen when the studies were designed and alternatives sought.

Despite the recent disappointment vicriviroc may still join the first in class CCR5 antagonist, Selzentry on the market as it will not be shelved according to Merck.

Merck continues to evaluate vicriviroc in treatment-naïve HIV-infected patients and patient enrollment has now been completed. In fact the experiences of Selzentry would suggest that the treatment-naïve population may represent the best target for vicriviroc.

Selzentry was initially approved for experienced patients, of whom only 50-60% are CCR5 tropic. As a result patients have to be tested prior to treatment to determine whether they are likely responders. The cost of testing presented a hurdle to Selzentry uptake. In contrast, approximately 80% of treatment-naïve patients have CCR5 trophic virus. Even though testing is still required its cost is less likely to represent wasted expense. In light of this, Merck is continuing the development of vicriviroc for treatment-naive patients.

Interestingly, the company is taking a novel approach in this setting by investigating vicriviroc in combination with Bristol-Myers Squibb's Reyataz (atazanavir) and eliminating the traditional nucleoside backbone. Concerns over NRTI toxicity have led to a renewed interest in such regimens, and prescribing two agents instead of the traditional three is also likely to have cost benefits. Moreover, this strategy may be highly effective in countering the threat from developmental fixed-dose combinations such as Gilead's Quad Pill and Gilead and Tibotec/Johnson & Johnson's Truvada/rilpivirine combination.

For further information on the HIV market see:

• HIV: Markets for Diagnostics and Therapeutics
• Forecast Insight: HIV - Cross-class fixed dose combinations drive continued growth
• Pipeline Insight: HIV - The Age of Convenience

Roche's new sub cutaneous formulation of Herceptin (trastuzumab) to offer increased benefit to early stage breast cancer patients

Herceptin was initially launched in 1999 for the treatment of HER2 positive metastatic breast cancer. Since that time lifecycle management has been stepped up and revenue for this leading monoclonal antibody hit 2.6 billion Swiss francs ($2.5 billion) during H1 2009. LCM activity has included the broadening of breast cancer indications; expansion to evaluate Herceptin as a gastric cancer therapy; and now the reformulation of Herceptin to allow subcutaneous administration.

Having received approval for the treatment of metastatic HER2 positive breast cancer, Roche soon after received expanded EU approval in June 2004 to include use in combination with docetaxel as a first-line therapy in patients who have not yet received chemotherapy. The 2006 approval was granted for the use in early-stage HER2 positive breast cancer following surgery and standard chemotherapy. The FDA granted approval for use in early stage breast cancer in 2008. Recent data reports that at least 80% of women with early stage HER2 positive breast cancer receiving one year of Herceptin were alive free of the disease at 5 years follow-up [press release].

LCM activity has also involved the development of Herceptin for the treatment of stomach cancer, with patients demonstrating improved survival when Herceptin was added to standard chemotherapy in the ToGA trial. This was particularly impressive in HER2 positive gastric cancers. The drug is in pre-registration in Europe for this indication and is expected to be filed soon in the US (for further information see Gastric Cancer - Targeted Therapies Home In On a Neglected Tumor Type)

Improving delivery of oncology therapies has received and will continue to receive considerable attention (see Drug Delivery in Cancer - Technologies markets and companies). In addition to broadening its indications, Roche hopes to draw on optimization through drug delivery development to encourage uptake of a more convenient formulation of Herceptin. This strategy could help to conserve its share of an increasingly competitive market, but may be challenging to implement due to concerns over compliance and financial incentives to prescribe intravenous cancer drugs.

Roche has invested roughly CHF190m ($183m) at two production sites to manufacture devices that will allow patients to self-administer a subcutaneous formulation of Herceptin (trastuzumab; Roche/Genentech/Chugai).

One site will supply the devices for a Phase III study which could support approval of the subcutaneous formulation. In this study, 552 patients with stage I-IIIc breast cancer will receive chemotherapy in combination with either subcutaneous or intravenous Herceptin before surgery, followed by 10 three-weekly infusions of subcutaneous or intravenous Herceptin. The study opened in October 2009 [Press release]

Herceptin's current intravenous formulation requires patients to receive the drug in hospital via a one-hour infusion. The subcutaneous formulation (developed in partnership with Halozyme Therapeutics) would increase convenience, allowing patients to self-administer the drug at home via a five-minute infusion. This is important given that Herceptin is administered for up to a year in early-stage breast cancer. Additionally, this would help to reduce costs associated with patient hospitalization and could improve the drug's side-effect profile by reducing infusion reactions.

Roche will hope that these factors increase brand loyalty and protect Herceptin's market share against potentially fierce competition from GlaxoSmithKline's oral HER-2 inhibitor, Tykerb (lapatinib), which is approved for metastatic breast cancer and is currently in Phase III trials for early-stage HER-2-positive breast cancer. Furthermore, switching patients to a subcutaneous formulation could help insulate against potential competition from biosimilar versions of intravenous Herceptin. As the lucrative monoclonal antibody market approaches maturity, such lifecycle management activities are likely to become increasingly common.

However, Roche could find it challenging to encourage uptake of subcutaneous Herceptin because it will make it more difficult for physicians to ensure patient compliance. Indeed, patient compliance can be a problem for some orally administered anticancer drugs. In the US, financial incentives for oncologists to prescribe intravenous drugs could further restrict uptake of the subcutaneous formulation. The ongoing Phase III study may therefore have to show that the more convenient subcutaneous formulation also has superior efficacy in order to drive appreciable uptake.

For further information on antibody therapeutics in oncology see Monoclonal Antibodies in Cancer Therapy 2009-2024

Until phase 3 data emerges, HCV PI share splits are pure guess work

Market research has been published reporting that 50% of US gastroenterlogists would treat HCV non-responders with telaprevir and concludes that this protease inhibitor will gain 70% of the market share.

I would treat any forecasts on how telaprevir and boceprevir will shape up against one another with respect to market share as pure guess work until phase 3 data is disclosed.

Sure, telaprevir has so far shown better efficacy in non-responders based on Phase 2 data. It is therefore hardly surprising that clinicians will favour telaprevir at this moment in this population. This could however change very rapidly as we progress through this year

in reference to:

"U.S. gastroenterologists will treat a larger proportion of treatment non-responder hepatitis C patients with Vertex/Tibotec/ Mitsubishi Tanabe’s telaprevir than Merck’s boceprevir"
- Vital Biopharmaceutical Insights and Analytics - Decision Resources (view on Google Sidewiki)