Release of triple-combo diabetes drugs imminent

Daewon Pharmaceutical and Hanmi Pharmarcuetical applies for the reimbursement of their 'stagliptin+dapagliflozin+metformin’ combination

Only 2 companies granted approval for triple combination therapy… in contrast to the 96 companies that own indications as dual combination therapy

"Challenging development process, impurity issues... Expansion of market expected in the long-term"

The release of the ‘triple combination therapies' appear to be in sight.

 

However, unlike the 2-drug combos that are already in fierce competition even in the pre-release stage, industry interest in 3-drug combos is currently at best lukewarm.

 

The pharmaceutical industry pointed to the relatively challenging development environment for triple combination drugs as well as the impurity issues that exist.

 

Nevertheless, there are predictions that in the long term, the paradigm for antidiabetic combos will shift from dual therapy to triple therapy combinations.

 

96 companies own 100 2-drug combos vs.

 

2 companies own 7 3-drug combos According to industry sources on the 6th, Daewon Pharmaceutical and Hanmi Pharmaceutical recently applied for the reimbursement of their 'dapagliflozin, sitagliptin, and metformin’ triple combination therapy for diabetes.

 

The drugs, Daewon Pharmaceutical's ‘Dapasita-M’ and Hanmi Pharm's ‘Sildapa M,' are expected to be released after September.

 

This is because the patent for the original sitagliptin drug Januvia will expire on September 1st.

 

Currently, the competition for antidiabetic combination drugs focuses on dual combinations.

 

As of the 5th, 96 pharmaceutical companies have received marketing approval for 100 dual combination products that combine SGLT-2 inhibitors and DPP-4 inhibitors.

 

This is in contrast to the fact that only 7 triple combination products from 2 companies have received marketing authorizations.

 

In the case of dual combinations, the dapagliflozin and sitagliptin combination accounts for the absolute majority with 93 products from 92 companies.

 

Many of these products are also expected to be released when the patent for Januvia expires.

 

While the interest in dual combination therapies is highly heated despite the possibility that a large amount of the products will be released at the same time, the attention towards triple combination therapies is still lukewarm.

 

Marketing approval state of SGLT2i + DPP4i combination therapy for diabetes

Considering the expanded reimbursement scope for diabetes treatments that had been granted earlier this year, the phenomenon is somewhat puzzling.

 

In May, the government limited the reimbursement scope for diabetes treatment to combinations of ▲SGLT-2 inhibitors, DPP-4 inhibitors, and Mmtformin, ▲SGLT-2 inhibitors, TZD, and metformin, ▲Some SGLT-2 inhibitors and sulfonylurea or in combination with insulin.

 

The SGLT-2 inhibitor and DPP-4 inhibitor combination, which includes a majority of the dual combination therapies, was not included in the reimbursement scope.

 

When prescribing to patients, doctors have to add metformin to the dual combination therapy drugs to receive reimbursement.

 

"Difficult combine metformin due to its large dose… Impurity issues and concerns in development cost also exist" The analysis is that multiple factors have contributed to this phenomenon.

 

The relatively complex product development is considered the primary reason among them.

 

The dose of metformin, which is much larger compared to the other two drugs, posed an obstacle.

 

The dose of dapagliflozin is set to 5mg and 10mg, while sitagliptin is set to 50mg and 100mg.

 

However, the dose of metformin is set much higher at 500mg, 750mg, and 1000mg.

 

Technically, combining the three ingredients is not difficult.

 

However, due to the significant differences in dosages of each ingredient, the stability of the final product may be somewhat compromised.

 

There are three main methods of combining the three ingredients: single-layered tablet, double-layered tablet, and coating Metformin with DPP-4 inhibitors and SGLT-2 inhibitors.

 

Among these methods, dapagliflozin and sitagliptin can be combined relatively thinly in single- and double-layered tablets due to their small doses.

 

As a result, there is a higher possibility that the two ingredients may not interact adequately.

 

The method of coating metformin to the duo is not significantly different, but achieving a uniform thickness is difficult.

 

This process poses certain challenges, such as the need for repeated bioequivalence tests to verify the uniform pharmacokinetic action of all ingredients.

 

The impurity issue is also another factor that makes the development of triple combination therapy challenging.

 

Among the three ingredients in the combination therapy, impurities have been detected in metformin and sitagliptin.

 

As a result, when manufacturing pharmaceuticals with these ingredients, companies must validate whether or not impurities exist and submit one year’s worth of safety data to the Ministry of Food and Drug Safety.

 

The so-called ‘1+3 joint bioequivalence’ system is also considered a factor that makes product development challenging.

 

Under the Pharmaceutical Affairs Act that was implemented in 2021, the number of consignor pharmaceutical companies is limited to three per one consignee.

 

This imposes a higher cost burden on small and medium-sized pharmaceutical companies in the development process compared to the past.

 

An official from the pharmaceutical industry said, "Companies that started product development before the implementation of the regulation may be fine, but the potential burden for companies considering new development after that is substantial." They further explained, "In the past when 10 to 20 companies could share the cost, each company had a smaller burden.

 

However, we can now only recruit up to four companies, which imposes a larger cost burden for each company." Another official stated, “The guideline set by the Ministry of Food and Drug Safety for the bioequivalence testing of combination therapies have become more stringent, requiring more extensive clinical trials than before.

 

If the total cost for developing a combination therapy is around KRW 6 to 8 billion, each company should now bear approximately KRW 2 billion.

 

This is not an easy decision for small and medium-sized pharmaceutical companies to make." "In the long term, triple combination therapies will increase… Numerous companies have already started development” However, the predominant forecast is that the number of companies venturing into the development of triple combination therapies will increase in the long term.

 

This analysis is based on the fact that triple combination therapy is considered more advantageous than dual combination therapies in terms of convenience in taking the medicine and applicability for reimbursement.

 

An industry official said, “While it is considered more challenging compared to dual combination therapies, the development and manufacturing of triple combination therapies is not inherently difficult.

 

The market will move in the direction of reimbursement, to triple combination therapies.” Another industry official added, "As dual combination therapies are not eligible for reimbursement and require additional intake of metformin, the demand for triple combination therapies is expected to steadily increase in the future.

 

Apart from Daewon Pharmaceutical and Hanmi Pharmaceutical, several other companies have already started or are considering the development of triple combination therapies."