Wednesday, February 24, 2010

Hope ahead for cervical cancer sufferers as Advaxis therapeutic vaccine shines

Advaxis' ADXS11-001 (formerly Lovaxin C) is a therapeutic vaccine in development for cervical cancer and potentially rare forms of head and neck cancer. Despite the launch of HPV vaccines, cervical cancer will remain a significant clinical problem in the developing world as well as in the developed world for the near future. Recent phase 1 data suggests that some advanced cancer patients inoculated with ADX11-001 have survived an astonishing 3 years. In today's blog we discuss these data and the cervical cancer/therapeutic vaccine field in general.

Invasive carcinoma of the cervix is the second most common cancer in women worldwide with over 450,000 new cases and 230,000 deaths annually, most of them occurring in developing countries. Persistent infection with high-oncogenic risk HPV, especially HPV16 and HPV18 are common underlying causes of malignant lesions, accounting for over 70% of Invasive carcinoma of the cervix and over 50% of high-grade precursor lesions.

According to Gynecological Cancers - Niche opportunities in advanced disease the incidence of cervical cancer is set to fall with the advent of prophylactic HPV vaccines. However cervical cancer will remain a problem for many years for two reasons. Firstly, prophylactic vaccines are unlikely to offer significant benefit to those women already infected with HPV. Consequently cervical cancer will continue to be a problem in women who were sexually active prior to the introduction of the vaccine. Secondly, worldwide implementation of such vaccines remains a challenge.

Given that cervical cancer will continue to be a problem it is particularly disappointing that few advances in this area of oncology have been witnessed over recent years. The best hope for women at risk of cervical cancer is early detection. Prognosis for women with early stage disease is good with cure rates of 60%-80% and fortunately there have been advances in diagnostics. For example DailyUpdates reported news from BD Diagnostics 2008 that the FDA had approved its FocalPoint GS imaging system [press release]. In May 2009 that Israeli company Zetiq demonstrated improvements over Pap staining. Pharmacological options remain in a state of relative inertia however.

According NCCN guidelines the first line approach to later stage disease remains radiotherapy with concurrent cisplatin-based chemotherapy. Response rates are quite low (20%-30%) and complete responses rare; overall survival with cisplatin is 6-9 months. Second line treatments are chemotherapeutic and associated with limited efficacy and significant toxicity. There is an obvious need for more targeted therapy that can offer improvements over cisplatin and possibly alternatives/adjuncts to surgery and radiotherapy.

With the exception of SRI International's cytotoxin, tirapazamine and PharmaMar's Zalypsis in (Phase 3 and 2 respectively) little development is being seen in the form of small molecules. Instead most activity is from the biologics sector. YM Bioscience is developing EGFR antibody, nimotuzumab, but by far the greatest efforts are currently being focussed on therapeutic vaccines (see World market for cancer vaccines 2007-2012).

To our knowledge four candidates are currently in the clinic for cervical cancer or the premalignant disease, cervical intraepithelial neoplasias (CIN). Inovio is developing a DNA vaccine targeting E6 and E7 proteins of HPV16 and HPV18, VGX-3100 for the treatment of CIN. This candidate is in Phase 1 development. More advanced is Roche's RG-3484, a modified vaccinia Ankara vaccine expressing E6 and E7 along with IL-2. Phase 2 trials opened last year, again focusing on CIN. A third vaccine is being developed by ISA Pharmaceuticals. In contrast to the Inovio and Roche vaccines this candidate is being developed for both CIN (Phase 2) and cervical cancer (Phase 1).

A recent paper (Radulovic et al, 2009) describes a fourth therapeutic vaccine in development for the treatment of cervical cancer, Advaxis' ADXS11-001 (formerly Lovaxin C). The technology being developed by Advaxis differs from other thereapeutic vaccines as it is the only live bacterial vaccine currently in clinical trials. It is based upon attenuated, bioengineered Listeria monocytogenes that provides very strong stimulation of innate immunity as well as both arms of the adaptive immune system, alters the tumor microenvironment to remove regulatory T cells (Tregs) and Myeloid Derived Suppressor Cells (MDSC) that are sources of immune inhibition, increases the pool of mature immune cells, facilitates migration of immune cells into tumors, and other effects.

Radulovic et al describe data from a Phase 1 study in which the vaccine was administered safely to women with cervical cancer and who had failed surgical, radiation and/or chemotherapeutic intervention. Patients were inoculated twice, at day 1 and day 22; the protocol required administration of antibiotics five days post-inoculation to attenuate the live vaccine. Adverse events were generally flu-like and transient.

The women recruited to the study would normally be expected to have a median survival of only 6 months with a 1 year survival of 5%. In this study, the median survival was doubled and the 1 year survival increased 10-fold. Remarkably, Advaxis recently reported updated data showing that 2 of 13 patients were alive at 3 years.

The data reported in the present study are fascinating, especially given the advance stage of disease and the fact that responses were seen with just two inoculations. Further studies, perhaps with booster vaccinations built into the protocols are awaited with great interest. In addition the promise shown in the present study suggests that evaluation of the vaccine in earlier stage CIN may be worthwhile. LeadDiscovery understands that further trials are planned for this year - one a Phase 2 study of cervical cancer patients; another a study of CIN patients.

Finally, a paper was published by Maxwell et al last year in the journal head and neck linking HPV to a rare head and neck cancer, nasopharyngeal carcinoma. We understand that a further trial is planned evaluating ADXS11-001 in this disease. This is not only of great clinical importance, it may also be of commercial importance. Advaxis failed to gain orphan drug status from the FDA last year on a cervical cancer indication. The company may be able to refile for an orphan indication on this new indication (for further information on head and neck cancer, including pharyngeal cancers read Stakeholder Opinions: Head and Neck Cancer).

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Monday, February 22, 2010

Javelin Pharmaceuticals' good fortunes continue - Ereska meets its pain-reduction end point but will it overcome the stigma of adverse events and drug

Javelin is one of a few companies that is reformulating existing drugs to address unmet needs in the pain management market. Candidates in development include Dyloject, Ereska and an intranasal morphine formulation known as Rylomine.

Dyloject was initially launched by Javelin in the UK in December 2007 for the treatment of acute pain, including postoperative pain. Dyloject differs from other IV formulations of diclofenac in that it employs a proprietary solubilizing agent that reduces irritation to veins and therefore does not require dilution or slow infusion. Movement towards the market in other geographies has taken longer with the company filing an MAA through the Mutual Recognition Procedure in 2009 and an NDA in December 2009. Last week we announced in DailyUpdates that the FDA had accepted the IND for review and that a PDUFA date had been set for October, 2010.

The NDA acceptance came after further good news for Javelin a few days earlier. On February 11th, 2010 the company announced that an external review of Phase III data for Ereska had found previously negative top-line results for its primary endpoint to be statistically significant. This randomized, placebo-controlled study assessed the safety and analgesic efficacy of repeated doses of Ereska over 6 hours in 259 patients with acute moderate to severe pain following orthopedic surgery. The primary end-point, pain intensity over the 6 hour period was reduced from 78.5 ± 12.4 to 47.3 ± 12.3 units (p=0.046)

While the revised analysis offers renewed hope for the company, doubts over Ereska must remain due to ketamine's association with drug abuse and its well-documented hallucinatory effects. Both factors represent key weaknesses in the market place, despite Ereska's proven efficacy.

Prior to the third-party reassessment of pain score measurements, Javelin Pharmaceuticals reported that Ereska (intranasal ketamine) had narrowly missed the principal goal of a late-stage trial. However, a third-party biostatistics company verified the presence of inconsistencies in the previously disclosed top-line results (based upon data captured by an external vendor). Indeed, the company has benefited from a share increase of around 6% since the announcement of the re-examined data.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been in use for over 25 years as an anesthetic, although is not approved for use as a pain reliever. Nevertheless, low-dose ketamine has been used off-label for the treatment of various pain complexes and the safety and efficacy of ketamine as an anesthetic and analgesic is well documented. According to IMS Health, ketamine achieved total sales of over $8m across the seven major markets (US, Japan, France, Germany, Italy, Spain and the UK) in 2008.

The market research company, Datamonitor believes that an FDA-approved formulation of ketamine for the treatment of moderate to severe pain will provide physicians with an accepted and regulated alternative to off-label use and opioids. Breakthrough pain, which affects approximately 42% of cancer patients across the seven major markets, is typically treated with opioids. In 2008, the opioids market was valued at an estimated $9.6 billion across the seven major markets and is forecast to grow in the future as a result of the launch of rapidly acting fentanyl products. However, opioids are associated with several adverse events and patients who use opioids chronically may display tolerance. For this reason, Datamonitor believes that there is a market for a non-opioid agent to treat breakthrough pain.

That said, pain specialists interviewed for today's featured report, stakeholder insight report into cancer pain, expressed concerns related to potential safety issues despite ketamine's potential as an alternative to opioids. Therefore, Javelin will need to carefully monitor the hallucinatory side effects of ketamine in future trials of Ereska. Pain specialists also proposed that use of ketamine and an opioid such as Actiq (fentanyl citrate; Cephalon) in combination represents an interesting avenue of research.

As the only non-opioid in the current breakthrough pain pipeline, and being of an intranasal formulation, Ereska is well positioned to compete against Cephalon's Actiq and Fentora in this market. However, a substantial challenge for Javelin will be to tackle the negative perception of ketamine as a dangerous drug that is associated with narcotics abuse. In order to overcome this barrier, Javelin would benefit from seeking the marketing resources of a larger company with experience in the narcotic analgesics market.

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