Antisense가 경구로 ??? 업계의 황당함이란…

올해 4월 24일 셀진 Celgene이 안티센스 제품 하나를 업프런트 7.5억불 (약 8천억원)을 주고 전세게 실시권을 취득했다. 

 

해당 제품 License Product: GED-0301(generic name : mongersen)

개발회사 Licensor: Nogra Pharma Limited (아일랜드 회사)

개발단계 Stage of devlopment: P2 완료단계

적응증  Indication: Chron’s desease  외

Upfront: $750m

Development and regulatory milestone: $815m

Sales (or commercial) milestone: $1,050m

 

그런데 특이한 점은 Nigra가 21개짜리 핵산올리고를 경구용으로 개발하고 있다는 것이다.

이에 대해 심지어 전문 블러거도 떄딱한 눈으로 보고 있다.

1) 1세대에 해당하는 phosphorothioate chemistry이다.

2) 표적은 smad7이라는 단백질을 발현하는 유전자이다.

3) 전임상 모델에서 효력이 있다는 논문이 나왔다.

Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis.

4) 임상1상에서 15명의 크론씨병 환자를 대상으로 안전성테스트를 했다.

– 일일 1회 7일간 복용

– 용량은 40, 80 그리고 160 mg/day

– 대체로 환자들에서 큰 부작용없었다.

위와 같은 자료가 있지만, 전문 블로거라고 할 수 있는 Dirk Haussecker 도 딱히 믿지는 못하겠지만, Celgene이 거금을 베팅했으니 그런가 보다 하는 것이다.

 

비밀은 21개짜리 안티센스 올리고를 위에서 버티면서 대장에서 방출이 되도록 enteric coating을 한 것이다.

생각해보면 CD나 Ulerrative Colitis가 굳이 약물의 전신분포가 필요없고 장내에서만 작용해되 된다는 점이 명확한데… 그걸 생각을 못했을까 생각케 한다.

 

사람들이 처음에는 셀진이 미쳤다고 생각했는데 임상2상 데이타 주요 결과만 발표했는데, 셀진 주가는 적절하게 올라줬다. 사람들이 이제 끄덕이는 분위기이다. 

결과는 아래와 같이 정리된다.

 

INTRODUCTION/OBJECTIVES:

Crohn’s disease (CD)-related inflammation is characterized by defective activity of the immunosuppressive cytokine transforming growth factor (TGF)-β1, due to high Smad7 (an inhibitor of TGF-β1) signalling. The effects of an oral, topically active Smad7 antisense oligonucleotide, Mongersen, were evaluated in a phase II study in patients with active CD.

AIMS & METHODS:

In a double-blind, placebo-controlled trial, the efficacy of Mongersen as induction therapy was evaluated in steroid-dependent or steroid-resistant patients (utilizing ECCO consensus definition) with active CD (CD activity index [CDAI] score 220-400). Patients were randomized to Mongersen 10, 40 or 160 mg/day or placebo for 2 weeks. The primary outcomes were clinical remission (CDAI score <150 at Day 15 and maintained for ≥2 weeks) and safety. Secondary endpoints included clinical response (CDAI score reduction of 100 points) at Day 28.

RESULTS:

Clinical remission was achieved by significantly greater proportions of patients receiving Mongersen 40 (55.0%) and 160 mg/day (65.1%) compared with placebo (9.5%; p<0.0001 for both). No significant difference in clinical remission was seen for 10 mg/day (12.2%) vs. placebo. The rate of clinical response was significantly greater among patients receiving 10 (36.6%), 40 (57.5%) or 160 mg/day (72.1%) of Mongersen vs. placebo (16.7%; p=0.039, p=0.0001 and p<0.0001, respectively). The rates of adverse events (AEs) and serious AEs (SAEs) were similar across groups. Nine SAEs occurred in 6 patients (placebo, n=1; Mongersen 10 mg, n=3; 40 mg, n=1; 160 mg, n=1). Most SAEs consisted of hospital admissions for CD-associated complications or symptoms, and included: pyrexia and cough (placebo); abdominal pain (n=2), CD worsening and pyrexia (Mongersen 10 mg); seton placement for perianal fistula and surgery for hemorrhoid thrombosis (Mongersen 40 mg); and thermal burn (Mongersen 160 mg).

CONCLUSION:

Induction therapy with orally administered, topically active Mongersen for CD was well tolerated; toxicities previously reported with systemically active antisense agents were not observed. Mongersen treatment resulted in significant improvements in clinical remission and response rates within 4 weeks of initiation of treatment (EUDRACT NUMBER 2011-002640-27).

 

이 결과는 어찌보면 Chemistry의 승리가 아니고 완전 disease biology의 승리라는 생각이 든다.  전혀 특별하지 않은 안티센스를 가지고 적절한 적응증에 대해서 적절한 제형을 만들어 대박을 냈다.

 

 

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