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Hepatocellular carcinoma is the most common type of primary liver cancer. The main risk factors include cirrhosis caused by hepatitis B/C and alcoholic fatty liver. Most patients in developed countries can be diagnosed in the early or mid-term of the disease, and receive curative surgery, local ablation treatment. Despite this, the recurrence rate of the disease is high, and patients with advanced disease usually receive systemic palliative care.

Current systemic treatments include three oral multi-target kinase inhibitors that have been approved, two of which are approved for first-line treatment.

Since its approval in 2007, Solafenib has been the standard treatment for hepatocellular carcinoma. Sorafenib was the first targeted drug to extend the overall survival of patients compared with placebo, but the objective response rate of this drug was extremely low, only 2%. Solafenib is mainly used for the treatment of patients with normal liver function.

 

In April 2017, the FDA approved rifafinib for the treatment of patients who have received sorafenib and progressed the disease, but rifafinib has a greater hepatotoxicity, and patients are suspended or reduced during clinical use. The condition of the dose is more common.

 

In March of this year, Japan approved another first-line drug, le vartinib (this drug was also approved by the US and EU in August this year). The PD-1 inhibitor Nivolumab is currently the only approved biologic drug for the treatment of hepatocellular carcinoma. Based on the high objective response rate of the drug and the high persistence of response, the FDA accelerated the approval of the drug in September 2017. Nivolumab is currently doing a Phase III head-to-head clinical trial with sorafenib (CheckMate-459).

 

R&D pipeline analysis

The development pipeline for hepatocellular carcinoma drugs is mainly composed of anti-angiogenesis inhibitors and immunological checkpoint inhibitors.

Cabotinib achieved the primary endpoint (total survival) in placebo in clinical trials compared to placebo. For patients treated with systemic therapy with sorafenib alone, cabozantini also prolonged patient survival compared with placebo.

 

Remolimumab is a drug that targets VEGFR2. The drug also reached its primary endpoint in phase III clinical trials (REACH-2). Similar to regifinib, cabotetini, patients treated with remollozumab after treatment with sorafenib also prolonged their overall survival. However, unlike other clinical trials, the baseline level of AFP in patients enrolled in the clinical trial of RERAMUMM (REACH) was high, and in subgroup analyses, it was found that for unselected patient populations, Compared with placebo, remoxonab did not significantly improve the overall survival of the patient.

Some key research drugs in the R&D pipeline

In addition to nivolumab, another PD-1 inhibitor, pembrolizumab, is also in Phase III clinical trials for patients with second-line therapy. In July of this year, the drug received the FDA’s priority review for the treatment of patients who had previously received treatment. Merck has submitted an NDA to the FDA based on Phase II clinical data.

 

Other PD1 inhibitors under investigation also include baekje Shenzhou/Xinji’s tislelizumab. Tislelizumab is also conducting a Phase III head-to-head clinical trial with Solafenib. The monotherapy of Spartalizumab and the combination with the c-Met inhibitor capmatinib are currently in clinical research.

 

The mechanism of action of bevacizumab and remollozumab is similar and can act on VEGF. The combination therapy of this drug with the PD-L1 inhibitor atezolizumab is currently in clinical research (IMbrave 150). The FDA has awarded this combination therapy breakthrough therapy certification based on data from this combination therapy Phase Ib clinical trial.

 

Another PD-L1 inhibitor, durvalumab, or a combination of the CTLA-4 inhibitor, tremelimumab, is currently in clinical trials to evaluate the treatment of patients with unresectable hepatocellular carcinoma.

Other combination therapies include the TGFβR1 inhibitor galunisertib in combination with nivolumab, remollozumab or sorafenib, and the phosphatidylserine inhibitor bavituximab in combination with pembrolizumab.

 

Market analysis

In 2017, the sales of patented drugs for the treatment of hepatocellular carcinoma in the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan totaled US$870 million. It is expected that the corresponding sales will increase to 40% by 2027. One hundred million U.S. dollars. Market growth will be driven by a variety of biopharmaceuticals and first-line treatments and adjuvant therapies for nivolumab.

It is expected that by 2027, PD-L1 inhibitors will surpass PD-1 inhibitors to become the highest-selling drug category in hepatocellular carcinoma (predicted to have sales of PD-L1 inhibitors of $1.7 billion in 2027). The use of durvalumab alone or in combination with tremelimumab for first-line treatment will contribute nearly half of the sales. It is estimated that by 2027, the sales of atezolizumab for first-line treatment will be around $530 million.

 

It is estimated that by 2027, the sales of PD-1 inhibitors will reach 1.5 billion US dollars, of which nivolumab will occupy the market of 1.1 billion US dollars. Although the first-line treatment-related patient population is the largest in advanced patients, about half of nivolumab’s sales will come from the field of adjuvant therapy.

 

Sales of CTLA-4 inhibitors ipilimumab and tremelimumab are expected to be significantly lower than PD-1/L1 inhibitors ($320 million). Sales of such drugs will be contributed by combination therapies in combination with PD-1 inhibitors. Although combination therapy is expected to increase the effectiveness of monotherapy, safety and patient tolerance issues will limit the market penetration of such combination therapies.

 

Anti-angiogenic drugs are the most important drug category in the field of hepatocellular carcinoma in 2017. Although some biopharmaceuticals and small molecule drugs will be approved for the market in the future, sales of such drugs are expected to peak and decline gradually in 2019. Biosimilars and generics will largely affect the future sales expectations of such drugs, and will also have a major impact on the overall market for hepatocellular carcinoma.

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