February 10, 2009 ViroPharma failure leaves CMV pipeline looking thin

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The failure of ViroPharma’s cytomegalovirus (CMV) treatment, maribavir, in a phase III trial, which could spell the end for the product, not only robs the US company of its biggest growth driver. It was also the most advanced CMV candidate under development, and the remaining research pipeline is thin, comprised mostly of early-stage vaccine approaches (see table below and ViroPharma's maribavir disappointment will sharpen focus, February 10, 2009).

CMV is a herpes virus that preys on those with weak immune systems, and treatments currently available to doctors are herpes polymerase inhibitors such as Roche’s Valcyte. Drugs including AstraZeneca's Foscavir and Gilead Sciences' Vistide are used for treating CMV in AIDS patients, however their high toxicity means new, safer approaches are in demand.

The virus can also attack very young children, it is estimated that approximately 86,000 new born babies are infected in the US and EU each year, causing 700 deaths and 17,500 cases of severe disability.

Clearly a vaccine presents itself as the most effective way of fighting CMV in most cases, hence the clinical stage research pipeline is comprised mostly of these prophylactic approaches.

Big player interest

The most advanced CMV candidate, behind maribavir, is Vical’s DNA vaccine, which is due to report top line results from a phase II trial in the second quarter of this year. Like ViroPharma, the company is working with transplant patients. Last November, an interim analysis of immunogenicity data for the first 33 transplant recipients revealed significant CMV-specific T-cell responses in those who received the vaccine; whether this translates into a clinically meaningful outcome remains to be seen.

The outcome is fairly pivotal for Vical, as a partner is being sought for the congenital indication. The drug has orphan status in the US, a definite plus point. With the current climate in mind the company has been laying off staff to conserve cash as it waits for data from a phase III metastatic melanoma candidate and the CMV vaccine.

At the end of 2008 Novartis licensed AlphaVax’s phase I CMV vaccine, in a deal worth $20m upfront, demonstrating that if Vical's trial succeeds, interest from big players is likely.

Other candidates include Sanofi-Aventis, which has not released much information about its vaccine, which is in phase IIa trials in congenital infection, with Glaxo and AstraZeneca also working on early stage vaccines.

More novel approaches exist in pre-clinical stages, but whether they will bear fruit remains to be seen. However, with maribavir looking doomed and the nearest treatment only in phase II trials, new treatments for CMV look some way off.

CMV pipeline

Indication Pharmacological Status Product Company Indication Summary Class (Current)

Phase III maribavir ViroPharma Imidazole CMV infections [Phase III]

Cytomegalovirus Phase II CMV vaccine Sanofi-Aventis CMV infections [Phase II] (CMV) vaccine

CMV infection prophylaxis Cytomegalovirus Cytomegalovirus Vical [Phase II]; CMV infection, AIDS vaccine (CMV) vaccine related [Abandoned in R&D]

General viral indications General viral indications [Phase II]; Smallpox treatment [Phase I]; CMV infections CMX001 Herpes Gilead [Phase I]; Human Phase I (hexadecyloxypropyl- polymerase Sciences/Chimerix papillomavirus (HPV) cidofovir) inhibitor infections [Phase I]; General respiratory tract infections [Pre-clinical]

Cytomegalovirus CMV infection prophylaxis CMV Vaccine Novartis/AlphaVax (CMV) vaccine [Phase I]

Cytomegalovirus CMV Vaccine AstraZeneca CMV infections [Phase I] (CMV) vaccine

Cytomegalovirus Cytomegalovirus CMV infection prophylaxis GlaxoSmithKline Vaccine (CMV) vaccine [Phase I]

Breast cancer [Phase II]; Non- small cell lung cancer (NSCLC) [Phase II]; Hepatitis C treatment [Phase I]; Solid tumour indications [Phase I]; Influenza [Pre-clinical]; CMV Pre- Peregrine infections [Pre-clinical]; HIV Bavituximab Anti-PS MAb clinical Pharmaceuticals treatment [Pre-clinical]; General viral indications [Pre- clinical]; General blood malignancies [Pre-clinical]; Prostate cancer [Pre-clinical]; Haemorrhagic fever, general [Pre-clinical]

HIV treatment [Pre-clinical]; MIV-410 Medivir NRTI CMV infections [Pre-clinical]

Cytomegalovirus CMV RNAi CytRx (CMV) RNAi CMV infections [Pre-clinical] Therapeutic therapeutic

Cytomegalovirus Anti-CMV Compound Inhibitex CMV infections [Pre-clinical] (CMV) agent

Cytomegalovirus CMV RNAi RXi (CMV) RNAi CMV infections [Pre-clinical] Therapeutic Pharmaceuticals therapeutic

Vakzine Projekt Cytomegalovirus CMV infection prophylaxis VPM2001 Management (CMV) vaccine [Pre-clinical]

Bone marrow transplantation PG36 Pharmagenesis Erythropoietin [Pre-clinical]; CMV infection, AIDS related [Pre-clinical]

Shingles [Phase II]; Glandular fever [Phase II]; CMV infections [Research project]; Chronic fatigue syndrome [Research Herpes Research ME-606 project]; Multiple sclerosis Medivir polymerase project (valomaciclovir) (MS) [Research project]; HIV inhibitor prophylaxis [Research project]; Herpes, genital [Abandoned in R&D]; Herpes, orofacial [Abandoned in R&D]

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