Biotech Values

[genisi]

Here's a basic read from Nature Reviews (January 2010) on the market. A bit out of date as development of motavizumab, the 2nd gen anti-RSV mAb derived from Synagis, was discontinued. Not sure how viable RSV604 is.

Respiratory syncytial virus market

By Shane Storey

See link for tables, figures, and ref. http://www.nature.com/nrd/journal/v9/n1/full/nrd3075.html

Respiratory syncytial virus (RSV) infections are the leading cause of viral death in infants, although RSV-related mortality has decreased since the development and approval of prophylactic antibodies. RSV also causes bronchiolitis, pneumonia and chronic obstructive pulmonary disease (COPD) exacerbations in the elderly, which lead to substantial rates of hospitalization and death1. RSV infection does not provoke lasting immunity, so human hosts experience lifelong cycles of infection and re-infection. Fortunately, RSV illness is mild in otherwise healthy people. The market for RSV treatments currently has only one, narrowly defined patient group: prematurely born infants at high risk of infection, who can be treated with immunoprophylactic antibodies. Over the next decade, the market could expand to reach at-risk adults and children suffering acute infections, probably through the availability of small-molecule and small interfering RNA (siRNA) agents (see Table 1 for selected RSV vaccine and antiviral development programmes). The development of RSV vaccines presents specific challenges, and their clinical use is currently a distant prospect.

Immunoprophylactic antibodies

Palivizumab (Synagis; MedImmune/Abbott) is a humanized murine monoclonal antibody against the RSV fusion protein that prevents the spread of virus to the lower respiratory tract2. It was approved by the FDA in 1998 and is licensed as a prophylactic agent for babies born prematurely at 35 weeks or less, and/or with congenital heart or lung disease. Palivizumab achieved blockbuster status (sales over US$1.2 billion in 2008), and MedImmune is likely to dominate this market for the next decade or more with second- and third-generation antibodies progressing through clinical trials. Motavizumab is an affinity-matured variant, which gives additional protection to the upper respiratory tract. In November 2008, MedImmune received a complete response letter to its biologics licence application (BLA) for motavizumab from the FDA and was expected to resubmit the BLA before the end of 2009. Further potency and lung bioavailability advances seem to have been achieved through directed molecular evolution, creating MEDI-557, which is now in Phase I testing3.

RSV vaccines

The approval of the first RSV vaccine is not expected before 2020. RSV vaccines require heightened safety evaluation by both sponsors and regulators because of the risk of enhanced disease. In the mid-1960s, a formalin-inactivated vaccine candidate caused the deaths of two infants who were enrolled in a clinical trial4.

To be cost-effective and gain reimbursement, RSV vaccines will probably need to be administered before the second month of life, because the population most at risk are babies aged 6 months or less. Candidate vaccines must also not reduce the safety or efficacy of the eight vaccines that are currently scheduled for routine administration in infants. MedImmune has the most advanced vaccine candidates: two formulations are now entering Phase I–IIa trials. MEDI-559 is a cold-passaged, live attenuated RSV that is being tested in 320 children aged 1 to <24 months. MEDI-534 is a human–bovine chimeric parainfluenza virus construct expressing the RSV fusion protein. Both candidates show promising safety profiles in Phase I testing and are expected to report efficacy data in 2012 (Ref. 5).

RSV antivirals

The availability of rapid (15-minute) RSV detection kits has opened a large market opportunity for RSV-specific antiviral drugs, which could be prescribed or administered in the general practice and emergency settings to treat acute RSV infections. The potential pool of patients (hospitalized or otherwise) who may seek RSV antiviral therapies is considerably larger than the group that is currently accessing palivizumab (Fig. 1).

RSV particles offer several targets to developers of small-molecule drugs. Many of the initial programmes targeted the fusion protein, perhaps because studies on palivizumab had provided such powerful molecular validation of that target. The attrition rate has been surprisingly high — several promising programmes have been discontinued after Phase I testing6 over the past 12–18 months, and there are now no fusion protein inhibitors beyond preclinical development. There are two reasons for this: the stringent requirements of the paediatric safety margin and the need to achieve a favourable pharmacokinetic–potency balance.

The two agents that have survived Phase I testing and are now undergoing Phase II trials have involved a different approach: both target the RSV nucleoprotein, but in different ways. RSV604 (Novartis/Arrow Therapeutics) is a benzodiazepine with oral availability, an excellent pharmacokinetic profile and potent activity7. Novartis is sponsoring Phase II trials of this compound in immunocompromised adults and has paediatric formulations in development. ALN-RSV01 is an siRNA compound that is designed to interrupt nucleoprotein synthesis and thereby inhibit viral replication8. Alnylam and Cubist Pharmaceuticals have conducted a randomized, placebo-controlled Phase II study of inhaled ALN-RSV01 in 24 lung transplant recipients with confirmed RSV infections. Only 7% of treated patients showed new or progressive bronchiolitis symptoms at 90 days post-treatment, compared with 50% in the placebo group. Although not designed to show efficacy, these results are encouraging, and ALN-RSV01 has the potential to become the first drug to be approved for RSV that is not restricted to prophylaxis in infants.

Future perspectives

The palivizumab market is large enough to attract interest from biogeneric developers, who may seek to enter the market from 2015, when the cornerstone palivizumab patents begin to expire. MedImmune aims to protect its market share with motavizumab, which shows superior efficacy to palivizumab in head to head Phase III studies9. The expansion of the RSV market will be enabled by products that satisfy specific needs in well-defined patient groups, as was achieved by palivizumab.

In the medium term, it will be interesting to see whether ALN-RSV01 can secure marketing approval for immunocompromised adults. The most lucrative target market is children under 2 years of age presenting with respiratory symptoms and confirmed RSV infections, for which the market demands an oral formulation.

Market indicators

Palivizumab is the only RSV-specific treatment on the market, and record sales of ~$1.35 billion are estimated for 2009 (Fig. 2). Motavizumab, an enhanced version of the product, is expected to receive approval in 2010 and eventually replace palivizumab in the market. MedImmune's antibody franchise is expected to expand if motavizumab confers an additional benefit and if the investigational product MEDI-557 can offer less frequent dosing. Motavizumab and ALN-RSV01 are the only compounds in development that have the potential to be approved before 2015, possibly followed by RSV604 in 2015. If approved, they will extend the RSV market to include elderly and/or immunocompromised patients and will increase market sales to more than $2 billion by 2015. Palivizumab is an expensive treatment, and it took several years before reimbursement support was granted outside the United States. Although the cost of acquiring palivizumab is the dominant expense in managing RSV, it has an attractive incremental cost effectiveness ratio, estimated at 11,000–21,000 per quality-adjusted life year gained10.

References...snip