Ge­net­ic Screen­ing Projects Make Japan A Ris­ing Op­tion For Clin­i­cal Tri­als

Re­cent ad­vances in ge­net­ic an­a­lyt­ic tech­nolo­gies like next gen­er­a­tion se­quenc­ing (NGS) and mul­ti­plex poly­merase chain re­ac­tion (PCR)  have re­duced both the costs and time need­ed to de­tect gene mu­ta­tions and have al­so made it pos­si­ble to de­vel­op per­son­al­ized can­cer treat­ments based on the re­sults of a ge­nom­ic analy­sis of in­di­vid­ual pa­tients. Tak­ing ad­van­tage of this, Japan’s largest phar­ma­ceu­ti­cal con­tract re­search or­ga­ni­za­tion (CRO), CMIC, is par­tic­i­pat­ing in two im­por­tant ge­net­ic screen­ing projects. Both are fo­cused on on­col­o­gy, which is the main ther­a­py where ge­net­ic screen­ing can ad­dress un­met needs in Japan and the wider Asia-Pa­cif­ic re­gion.

The first project, HM-SCREEN-Japan, start­ed in 2019 and is fo­cused on acute myeloid leukaemia (AML, or blood can­cer). The ul­ti­mate aim is to ex­am­ine gene mu­ta­tions in Japan­ese AML pa­tients and use the da­ta to pro­mote the de­vel­op­ment of drugs to treat it.

The think­ing be­hind it re­flects some re­cur­rent is­sues in drug de­vel­op­ment in the Japan­ese mar­ket. “In Japan, there are prob­lems of drug-lag, in which new drugs de­vel­oped over­seas are in­tro­duced late, and drug-loss, where they are not in­tro­duced at all,” says Dai Na­ga­ki, clin­i­cal project man­ag­er for CMIC’s CRO busi­ness.

“There are sev­er­al pos­si­ble rea­sons for this sit­u­a­tion. In the case of AML, drug de­vel­op­ment pro­gress­es be­cause of gene mu­ta­tions that are matched with par­tic­u­lar drugs. The num­ber of can­di­dates for per­son­al­ized treat­ment in Japan is lim­it­ed be­cause of the small num­ber of AML pa­tients com­pared to the US. There­fore, we as­sume that over­seas com­pa­nies are hes­i­tat­ing to con­duct de­vel­op­ment in Japan.”

Two stud­ies have been con­duct­ed so far with­in HM-SCREEN Japan and some re­sults have been re­port­ed at sci­en­tif­ic meet­ings, in­clud­ing the Amer­i­can So­ci­ety of Hema­tol­ogy An­nu­al meet­ing in 2020. The com­mon types and some of the spe­cif­ic char­ac­ter­is­tics of gene mu­ta­tions in Japan­ese pa­tients with AML have be­come clear­er but there are few drugs avail­able at present that can ad­dress these mu­ta­tions. There­fore, Na­ga­ki says, “We need to con­sid­er how we can en­cour­age the de­vel­op­ment of such drugs in Japan and are look­ing to col­lab­o­rate with oth­er com­pa­nies to de­vel­op new drugs out of the re­sults of HM-SCREEN-Japan.”

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Wider scope of sec­ond project

In Jan­u­ary 2023, CMIC be­came the first CRO to join the LC-SCRUM-AP screen­ing project on non-small cell lung can­cer, which is joint­ly run by Na­tion­al Can­cer Cen­ter Hos­pi­tal East and Pre­ci­sion Med­i­cine Asia (PRE­MIA). This project start­ed as LC-SCRUM-Japan but has since been widened out to the wider Asia-Pa­cif­ic re­gion.

Study sites are cur­rent­ly be­ing ac­ti­vat­ed and the in­fra­struc­ture es­tab­lished. Mul­ti­ple in­sti­tu­tions in Thai­land, Malaysia, Viet­nam, Sin­ga­pore, In­done­sia, Aus­tralia, and Tai­wan, will par­tic­i­pate. The time­line is not ful­ly de­cid­ed yet, but sub­ject en­rol­ment has al­ready been ini­ti­at­ed at the in­sti­tu­tions in Thai­land, Malaysia, and Tai­wan.

“Across dif­fer­ent coun­tries, ge­net­ic mu­ta­tions can vary with eth­nic­i­ty and the de­gree of in­ter­ven­tion, among oth­er things,” Na­ga­ki says. “De­pend­ing on the char­ac­ter­is­tics of the agents im­port­ed for use in clin­i­cal tri­als, there could be a very low ex­pres­sion rate of ge­net­ic mu­ta­tions, and this could be a big hur­dle with­in the tri­als. If de­cen­tral­ized clin­i­cal tri­als (DCTs) are rec­og­nized and im­ple­ment­ed in Asian coun­tries, a pa­tient lo­cat­ed in non-ac­tive-site coun­tries could par­tic­i­pate in the clin­i­cal tri­als. We are bring­ing over the screen­ing bases we had in LC-SCRUM-Japan to oth­er coun­tries as well.”

“The ul­ti­mate aim is to de­vel­op pre­ci­sion med­i­cine in Asia-Pa­cif­ic by es­tab­lish­ing a ge­nom­ic screen­ing in­fra­struc­ture for the re­gion,” says Yu­ki Kin­u­gasa, clin­i­cal leader at CMIC. “This will make it pos­si­ble to con­duct ge­net­ic screen­ing on a larg­er scale and ac­cel­er­ate the de­vel­op­ment of new mol­e­c­u­lar tar­get­ing agents for var­i­ous ge­nom­ic al­ter­ations.”

“Based on the ac­cu­mu­lat­ed data­base of gene mu­ta­tions, CMIC can sup­port phar­ma­ceu­ti­cal com­pa­nies in de­vel­op­ment strate­gies for new drugs. For ex­am­ple, we could sug­gest coun­tries and study sites where clin­i­cal tri­als should be con­duct­ed, based on the data­base. If a spe­cif­ic gene mu­ta­tion is iden­ti­fied by LC-SCRUM-AP, the pa­tient may be able to en­roll in the tri­al. And, de­pend­ing on the sit­u­a­tion, pa­tients might be able to re­ceive un­ap­proved drugs by join­ing tri­als.” 

In the longer term, ge­net­ic screen­ing stud­ies like these may help to make some drugs more wide­ly avail­able in the re­gion. Many drugs tar­get­ing al­ter­ations in EGFR, ALK, ROS1, BRAF, NTRK, MET, RET, and KRAS have been ap­proved in Japan so far, but the pic­ture is patchy else­where in Asia-Pa­cif­ic. For ex­am­ple, lung can­cer pa­tients in Japan usu­al­ly un­der­go tests for the rel­e­vant gene mu­ta­tions, while in Thai­land er­lotinib is the on­ly ap­proved EGFR in­hibitor, and ROS1, RET and oth­er gene mu­ta­tions are not test­ed.

Pre­ci­sion med­i­cine, adds Kin­u­gasa, is not as wide­ly un­der­stood and es­tab­lished in some Asia-Pa­cif­ic coun­tries as it is in the US and Japan. By in­te­grat­ing the data­bas­es of LC-SCRUM-AP and LC-SCRUM-Asia, suc­ces­sor to LC-SCRUM-Japan, and cre­at­ing a clin­i­cal ge­nom­ic data­base for the re­gion, “large-scale, re­al-world da­ta will be ac­cu­mu­lat­ed, and it is ex­pect­ed to con­tribute to the de­vel­op­ment of pre­ci­sion med­i­cine.”

More­over, he con­tin­ues, the ex­pres­sion rate and speci­fici­ty of gene mu­ta­tions vary de­pend­ing on eth­nic­i­ty and re­gion. “It’s im­por­tant to treat pa­tients ac­cord­ing to the char­ac­ter­is­tics of new drugs. The fre­quen­cy of each of these ge­nom­ic al­ter­ations is rare, so that of­ten makes it im­pos­si­ble to con­duct tri­als ef­fi­cient­ly. When DCT and oth­er tech­nolo­gies de­vel­op more, it may be pos­si­ble for pa­tients from oth­er coun­tries to par­tic­i­pate in this study, so it’s very im­por­tant to ac­cu­mu­late da­ta.”

Takashi Asahi, ex­ec­u­tive vice pres­i­dent for the CRO busi­ness at CMIC, adds: “There are lots of iden­ti­fied gene mu­ta­tions. With this in mind, it is im­por­tant for the in­ves­ti­ga­tor and us to iden­ti­fy the gene mu­ta­tion fast when the clin­i­cal tri­al for new drug is start­ed, as the pa­tient will get the op­por­tu­ni­ty to take the pre­ci­sion med­i­cine. In ad­di­tion, if the PCR is neg­a­tive, PRE­MIA will con­duct NGS. There­fore, even if the spe­cif­ic mu­ta­tion is not iden­ti­fied by PCR, an­oth­er mu­ta­tion will be iden­ti­fied by NGS, and the pa­tient will be able to join the new clin­i­cal tri­als. That’s why it is im­por­tant for us to con­duct these kinds of tri­als.”

Op­por­tu­ni­ties in Japan

CMIC it­self sees op­por­tu­ni­ties aris­ing for non-Japan­ese com­pa­nies in clin­i­cal tri­als in Japan as a re­sult of these stud­ies. For ex­am­ple, bone mar­row trans­plants are still the first line of treat­ment for AML, but more than half of the pa­tients can­not get these for rea­sons of age and have to take what­ev­er drug treat­ments are avail­able. With Japan’s age­ing pop­u­la­tion, the num­ber of AML pa­tients need­ing drug treat­ment will grow and this could be an at­trac­tive mar­ket for over­seas com­pa­nies. There is al­so po­ten­tial for ex­pand­ing the scope of re­search to oth­er types of lym­phoma.

“The sites par­tic­i­pat­ing in HM-SCREEN are treat­ing a large num­ber of AML pa­tients and are ac­tive in re­search and oth­er clin­i­cal tri­als,” Na­ga­ki says. “Al­though the num­ber of AML pa­tients is small, CMIC can use the da­ta ob­tained from HM-SCREEN to con­sult on re­al­is­tic de­vel­op­ment strate­gies, re­quest pa­tient re­fer­rals to par­tic­i­pat­ing study sites when con­duct­ing tri­als, and of­fer more to phar­ma­ceu­ti­cal com­pa­nies who are con­sid­er­ing en­ter­ing the Japan­ese mar­ket and want to get re­al­is­tic da­ta on the num­ber of pa­tients and spe­cif­ic mu­ta­tions. In ad­di­tion, since many of the par­tic­i­pat­ing med­ical in­sti­tu­tions in HM-SCREEN are ca­pa­ble of con­duct­ing ear­ly phase tri­als, CMIC can in­tro­duce the in­ves­ti­ga­tor’s site to con­duct the lead-in study to Japan, in­clud­ing first-in-hu­man (FIH) with HM-SCREEN.”

Asahi notes that the Japan­ese PM­DA has been slow­er to ap­prove to new drugs than the US FDA or the EMA in Eu­rope. This sit­u­a­tion has been im­proved, al­though PM­DA con­sul­ta­tions take longer. With re­gard to clin­i­cal tri­als net­work prepa­ra­tion there are some chal­lenges, such as the time is need­ed to trans­late doc­u­ments in­to Japan­ese.

About half of ap­proved drugs in the US are still not ap­proved in Japan. This sit­u­a­tion could change if a pa­tient’s gene mu­ta­tion could be iden­ti­fied, and over­seas phar­ma­ceu­ti­cal com­pa­nies could ac­cess a large data­base. In the last few years, CMIC has seen an in­creas­ing num­ber of in-coun­try clin­i­cal care­tak­er (IC­CC) projects where it ac­cess­es clin­i­cal care in Japan for over­seas com­pa­nies.

The biotechs who are in­creas­ing­ly dom­i­nat­ing in the de­vel­op­ment of new drug can­di­dates rarely have op­er­a­tions in Japan and have gen­er­al­ly shied away from Japan for test­ing be­cause it not cheap or fast. Par­tic­u­lar­ly in view of the re­cent pass­ing of the In­fla­tion Re­duc­tion Act in the US, Asahi says, the Japan­ese health care mar­ket may be more open to them. “There­fore, we need to tell peo­ple that the Japan­ese mar­ket may be more at­trac­tive than they think.”

The COVID-19 pan­dem­ic has al­so con­tributed in­di­rect­ly to­wards cre­at­ing new op­por­tu­ni­ties for com­pa­nies look­ing to con­duct clin­i­cal tri­als in Japan. At the start, when the gov­ern­ment first an­nounced a state of emer­gency, there was a tem­po­rary sus­pen­sion of pa­tient en­rol­ment and de­lays in ini­ti­at­ing new clin­i­cal tri­als. Pa­tients be­came un­able or un­will­ing to vis­it study sites, while clin­i­cal re­search as­so­ciates (CRAs) were of­ten un­able to do so.

“Each CMIC tri­al man­ag­er act­ed based on the dis­cre­tion of the spon­sor, re­fer­ring to the guid­ance from PM­DA. Now that COVID-19 has sub­sided, ef­fi­cient mon­i­tor­ing meth­ods re­main,” says Kin­u­gasa. “For ex­am­ple, they act­ed to es­tab­lish re­mote mon­i­tor­ing en­vi­ron­ments, such as re­mote source doc­u­ment ver­i­fi­ca­tion (SDV) and on­line meet­ing, to con­tact and man­age a study site re­mote­ly with­out vis­it­ing it. There are no more ob­sta­cles to con­duct­ing mon­i­tor­ing in these ways, which were al­most un­known be­fore COVID. All of these new ways of con­duct­ing tri­als are con­tin­u­ing in Japan and it is a pos­i­tive thing for us and our po­ten­tial over­seas clients.” ¹

Con­clu­sion

Ad­vances in ge­net­ic screen­ing are open­ing up many new av­enues in drug de­vel­op­ment. Two on­go­ing ge­net­ic screen­ing projects in Japan and Asia-Pa­cif­ic are prime ex­am­ples of this, tar­get­ing ther­a­pies where there are con­sid­er­able un­met needs that are cer­tain to grow. These projects and oth­ers like them will al­so cre­ate op­por­tu­ni­ties for phar­ma­ceu­ti­cal com­pa­nies to con­duct more clin­i­cal tri­als in Japan and the Asia-Pa­cif­ic re­gion.

Ref­er­ence:

1. White Pa­per, Evolv­ing Trends of De­cen­tral­ized Clin­i­cal Tri­als in Japan, De­cem­ber 2020

• CMIC CEO/COO lead­er­ship in­ter­view ar­ti­cle
• Round­table Dis­cus­sion Re­port: The Ben­e­fits of Clin­i­cal Tri­als in Asia Are Sig­nif­i­cant if Done Right.