The story of CEL-SCI and combination immunotherapy Multikine

CEL-SCI Corporation (NYSE: CVM) is a biotechnology company focused on cancer immunotherapy. Its lead investigational therapy Multikine (Leukocyte Interleukin, Injection) is enrolling patients for a pivotal phase III clinical trial against head and neck cancer.

In the late 1970s, Maximilian de Clara, the company’s founder, believed the theory that the immune system could fight cancer. He funded the early Multikine research at the Max Plank Institute in 1978, and founded CEL-SCI around the idea of Multikine in March 1983.

Multikine is a combination immunotherapeutic agent, consisting of a mixture of naturally occurring cytokines, including interleukins, interferons, chemokines and colony-stimulating factors. It is designed to directly affect both the tumor cells themselves and activate an anti-tumor immune response.

CEL-SCI was cash poor and struggling to survive until 1992. A small pilot plant to manufacture Multikine on a sufficient scale suitable for conducting widespread studies in humans was constructed in 1993.

From 1994 to 2000, CEL-SCI completed a series of phase I and phase II clinical trials with Multikine. Unfortunately, CEL-SCI was sent back into survival mode as funding dried up.

The “proof of concept” phase II clinical trial of Multikine has published in JCO (J Clin Oncol. 2005, 23, 3421-3432.).

Thirty-nine oral squamous cell carcinoma (OSCC) patients participated in this phase II study (19 Multikine-treated patients and 20 historical controls). Multikine was injected five times a week for three weeks around the tumor as well as the local draining lymph nodes. A single intravenous infusion of low-dose cyclophosphamide (300 mg/m2) was given three days before the first Multikine administration. Surgery was performed between days 14 and 54 after the end of treatment.

Of the 19 patients treated with Multikine, 2 patients had  tumors that completely disappeared; 2 patients had a tumor reduction of greater than 50%; 4 patients had a tumor reduction of 30-50%. This is an overall response rate of 42%. Multikine appeared to have caused the disappearance of about half of the cancer cells present at surgery.

Follow-up studies showed an approximate 33% improvement in overall survival at 3.5 years after surgery. The overall survival rate at 3.5 years from surgery of 19 subjects receiving Multikine is 63.2%, while the overall survival rate in the same cancer population gleaned from the literatures is 47.5%.

Although the overall response rate and survival rate are impressive, no definitive conclusions can be drawn from these data resulted from only 19 subjects. Further research is required to confirm these results.

In 2005, Canada became the first country to clear Multikine to enter phase III trials. The FDA enabled Multikine to enter Phase III trials and granted orphan drug designation in 2007. The orphan drug status provides seven years marketing exclusivity, tax incentives (up to 50% of R&D costs), and financial subsidization ($350,000 per year up to 3 years).

Because Multikine is a complex biologic of multiple cytokines that must be manufactured in a cold-fill facility, it is vital to guarantee the consistent quality of Multikine in the phase III trial. In 2006-2007, CEL-SCI raised $8.3+15 million and built a 73,000 square foot manufacturing facility.

The financial crisis of 2008-2009 hit CEL-SCI again. The validation of the manufacturing facility and the start-up of the phase III clinical trial were delayed. Finally, the phase III open-label, randomized, controlled, multi-center study was initiated in 2010.

The global pivotal phase III study is planned to enroll approximately 880 subjects in about 100 centers in 20 countries. The phase III trial is designed to compare Multikine combined with standard therapy (surgery + radiotherapy/chemotherapy) vs.  standard therapy alone. The primary endpoint is a 10% overall survival advantage after 3 years.

In April 2013, in order to speed up enrollment, CEL-SCI hired two new CROs—- Ergomed and Aptiv Solutions, substituting the prior CRO—- PharmaNet (acquired by inVentiv Health Clinical in 2011). Full enrollment in the phase III study is anticipated to occur by the end of 2015. According to an article by Michael Morhamus, inVentiv only enrolled 117 patients in 3 years.

An October 15, 2013 press release stated that Ergomed will assume $10 million R&D costs and will be paid by an agreed single digit percentage of Multikine’s sales. CEL-SCI has also partnered with Teva Pharmaceuticals, Orient Europharma, and Byron Biopharma to bring Multikine to the market in Middle East, Asian, and South Africa, respectively.

In October 2013, CEL-SCI signed a collaborative R&D agreement with the U.S. Navy for the treatment of HIV/HPV co-infected patients with anal warts. Eight days later, CEL-SCI signed a co-development and profit sharing agreement with Ergomed for the treatment of HIV/HPV co-infected women with cervical dysplasia. These collaborations allowed CEL-SCI to pursue additional indications for Multikine.

According to Wikipedia, there are 0.5 million new cases of head and neck cancer a year worldwide. About 20% of these are in the US and EU and are suit for adjunctive treatment with Multikine. Providing the price is $50,000 per regimen, the annual sales would be 5 billion.

The current market capitalization of CEL-SCI is very low, only $70 million. Positive phase III results of Multikine will put CEL-SCI at a 15 billion market capitalization, which is 200 times higher than that of today.

Maximilian has worked for Multikine for nearly 40 years. Due to lack of funding, too much time was wasted. CEL-SCI got the positive phase II results in 2004, however, the initiation of phase III study delayed until 2010. This is the norm for many small biotech companies but not CEL-SCI’s fault. They even worked without salaries and funded CEL-SCI with their own money in difficult times.

Luckily, CEL-SCI reached an important milestone in July 2014 with total patient enrollment reaching 232, which is over one-quarter of the total 880 patients. If all goes well, the end of phase III study would be December 2017, resulting in an FDA approval in 2019.

A key patent covering Multikine is WO2005007086, which expires in 2024. The orphan drug designation will give 7 years marketing exclusivity. CEL-SCI will be the only provider of Multikine for many, many years because it is not easy to develop biosmilars for such a complex biologic.

In a word, Multikine has the potential to be a new blockbuster. However, there is no doubt that this is a high-risk investment. The phase III study involving 880 patients, to demonstrat a 10% overall survival advantage, is based on the positive phase II results of 19 patients, just 19 patients. Moreover, the specific mechanism by which Multikine exerts its therapeutic action is not well defined.

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