Hanmi’s diabetes pipeline still standing in the storm

Sanofi announces plan to maintain the pipeline but to find commercialization partner

Surviving a rough R&D pipeline shake-up

Largest license-out deal in Korea to date, but agreement amended twice already

Hanmi Pharmaceutical’s efpeglenatide with the title of the biggest license-out deal to date is going through harsh times before reaching the finish line.

 

The company’s unbent commitment for the pipeline kept it alive, despite amending the license out agreement twice and the partner company shifting R&D pipeline focus.

 

Although it seems to have international clinical trials on their way unaffected, the company is now concerned of change in global commercialization partner.

 

Headquarters of Hanmi Pharmaceutical

On Dec.

 

10, Hanmi Pharmaceutical’s stock price closed at 298,000 won with 6.88 percent drop from the day before.

 

Hanmi Science also took a 4.57-percent fall.

 

Experts see that news of Hanmi Pharmaceutical’s partner company, Sanofi looking for a partner to launch efpeglenatide may have intimidated the investors.

 

◆Efpeglenatide surviving albeit Sanofi’s R&D pipeline shake-up In fact, efpeglenatide’s development timeline has not been changed.

 

Sanofi broke a news of acquiring a U.S.-based oncology R&D company Synthorx for USD 2.5 billion (approximately three trillion won) on Dec.

 

9, and elaborated its plan to shift the focus of R&D pipeline and management style.

 

Sanofi official stated it would prioritize investment on oncology, rare disease, blood disorder and neurology, while it would cease researches on diabetes and cardiovascular disease.

 

However, the multinational company’s news also included its plan to complete ongoing Phase 3 clinical trials of efpeglenatide, but not to pursue a efpeglenatide launch.

 

At face value, Sanofi means to not commercialize efpeglenatide, but it also means the pipeline survived another major pivot in Sanofi’s R&D pipeline.

 

The candidate drug is the only diabetes treatment pipeline among five investigational drugs the multinational company plans to submit the U.S.

 

Food and Drug Administration (FDA) New Drug Application (NDA) for in two years time.

 

A Sanofi executive stressed “It was the best decision for the successfully launch of efpeglenatide while maximizing the productivity of our research engine.

 

It was irrelevant to efficacy and safety of the substance, and it would make no changes on license-in agreement with Hanmi Pharmaceutical”.

 

Technically, efpeglenatide proved its potential to Sanofi’s new CEO, Paul Hudson appointed last August, despite his firm commitment to reprioritize R&D pipeline.

 

In the year, Sanofi suddenly stopped research in a trigonal GLP-1/GIPR/GCGR agonist, SAR441255.

 

And the French company also has paid back upfront fee to exit a 300-million-dollar partnership deal over SGLT1/2 dual inhibitor Zynquista (sotagliflozin) signed in 2015.

 

‘New Drug Application Submission Timeline 2019-2023’ unveiled during 3Q performance presentation by Sanofi

◆Amending license-out agreement twice, two LAPSCOVERY medicines returned Starting with the license-out agreement, efpeglenatide has gone through a series of ups and downs.

 

Efpeglenatide, a GLP-1 injection for type 2 diabetes, is a bio drug candidate that extended once-daily administration interval to once-weekly and even once-monthly.

 

It incorporated Hanmi Pharmaceutical’s key platform technology, ‘LAPSCOVERY’.

 

LAPSCOVERY, or Long Acting Protein/ Peptide Discovery platform technology prolongs the duration of biologics’ short half-life to reduce administration frequency and dose, which would ultimately reduce adverse reaction and improve efficacy.

 

Chemically conjugated biologics and protein ‘LAPS-carrier’ amplifies duration of the substance’ effect in human body and maintains the effect for maximum one month even with a small amount.

 

In November 2015, Hanmi Pharmaceutical signed a license-out agreement with Sanofi on efpeglenatide, which still to this date is the biggest deal in the history of Korean pharmaceutical industry.

 

The 2015 deal transferred technology of a EUR 3.9 billion-worth Quantum Project (efpeglenatide, long-acting insulin, and efpeglenatide with long-acting insulin) to Sanofi.

 

The upfront fee alone was 400 million euro.

 

But after closing the deal, a number of unexpected changes were made.

 

In December of 2016, Hanmi Pharmaceutical amended the agreement to drop one of the drug candidates from the ongoing technology transfer project.

 

Out of three drug candidates, Sanofi decided to return license over the long-acting insulin.

 

Agreement terms on the long-acting insulin combination was also changed so that Sanofi would acquire it after Hanmi Pharmaceutical develops it for a certain period of time.

 

As a result, Hanmi Pharmaceutical paid back 196 million euro out of Sanofi’s 400-million-euro upfront payment.

 

The milestone payments were also affected and the overall deal was shrunk by over one billion euro, down to 2.82 billion euro.

 

Regardless of the reduction, the upfront fee and overall scale of the efpeglenatide deal is still historic record high within the Korean pharmaceutical industry.

 

Hanmi Pharmaceutical-Sanofi agreement revised in June (Source: Financial Supervisory Service)

In June, however, Hanmi Pharmaceutical and Sanofi agreed to amend the agreement once again.

 

Hanmi Pharmaceutical lowered the maximum co-research expense from 150 million euro to 100 million euro with about 50 million euro (approximately 65 billion won) cut.

 

The first amendment actually included a clause for Hanmi Pharmaceutical to contribute 25 percent of efpeglenatide R&D expense, which was supposed to be covered entirely by Sanofi.

 

And Hanmi Pharmaceutical set the research expense cap at 150 million euro.

 

In just about two years, Hanmi Pharmaceutical was able to revise the clause added in 2016 to be more favorable to them.

 

When amending the agreement for the second time, Hanmi Pharmaceutical also postponed its payment period of clinical trial expense.

 

Initially, Hanmi Pharmaceutical was supposed to pay when Sanofi quarterly billed for efpeglenatide’s clinical expense.

 

The additional expense of 40 million euro out of 68.5 million euro would be billed on an earlier date between September 2022 and submission date of Biologics License Application (BLA) to FDA.

 

The bill is to be cleared by Hanmi Pharmaceutical within 15 days.

 

The rest of 28.5 million euro would be paid on earlier date, either in September 2023 or the FDA approval date.

 

Basically, Hanmi Pharmaceutical is to pay Sanofi whenever efpeglenatide development achieves a milestone.

 

When Sanofi initiated large scale clinical trials on efpeglenatide, the expense soared more than expected.

 

But then Sanofi seems to have accepted Hanmi Pharmaceutical’s request to lower its contribution in clinical expense.

 

Meanwhile, risk factors in LAPSCOVERY technology have been raised.

 

Janssen signed a technology transfer deal on JNJ-64565111, a candidate diabetic obesity drug, but it had to suspend clinical trial due to production delay.

 

In July, Janssen returned its license on JNJ-64565111 and the license-out agreement covering two candidate drugs based on LAPDISCOVERY technology fell through.

 

Spectrum Pharmaceutical’s in-licensed Rolontis, a neutropenia treatment, is the first LAPSCOVERY-applied medicine to get so close to commercialization.

 

A U.S.-based Spectrum Pharmaceutical filed for FDA approval on Rolontis at the end of last year, but it dropped the BLA in March as the authority ordered for more supplementary data.

 

The application was submitted again in October.

 

◆ Five out of two efpeglenatide clinical trials completed selecting participants Currently, the efpeglenatide development is going smoothly.

 

Two years after signing the deal, Sanofi officially unveiled a detailed plan on efpeglenatide at the end of year 2017.

 

By the end of 2017, Sanofi initiated the first Phase 3 clinical trial to compare efpeglenatide and placebo, and in April last year, the company initiated a large-scale Phase 3 trial to test efficacy and safety in treating cardiovascular diseases.

 

Another Phase 3 trial was initiated since September last year to compare efpeglenatide and competing product Trulicity (dulaglutide) as a combination therapy with Metformin.

 

In October last year, a protocol on combination therapy with efpeglenatide and basal insulin was registered, and in December same year, the fifth Phase 3 trial was initiated to confirm the drug treating Type 2 diabetic patients who cannot control glucose level either after Metformin single therapy or Metformin and sulfonylureas combination therapy.

 

The overall target number of sample is 6,340.

 

As of now, two out of five Phase 3 trials on efpeglenatide have gathered sufficient number of participants.

 

Most recently, placebo-comparing Phase 3 trial AMPLITUDE-M has gathered targeted number of patients.

 

The investigational drug’s key trial, AMPLITUDE-O testing effect of efpeglenatide on cardiovascular outcomes has registered more than planned number of participants of 4,076 patients in June.

 

A Hanmi Pharmaceutical official stated, “Sanofi has promised to concentrate on completing numerous Phase 3 trials currently ongoing to develop efpeglenatide successfully”.

 

Two Phase 3 efpeglenatide trials have registered enough number of patients (Source: ClinicalTrials.gov)