GEN003 Phase 2b 治験結果、中間発表！

暑い日が続きますが、皆様如何お過ごしでしょうか？

以前の投稿から大分時間が経ってしまいました… (''_'') ちょっと仕事の関係で忙しい時期が続いておりましたので、少し遠ざかっておりましたが、またよろしくお願いいたします (^_-)-☆

さて、今回の投稿ですが、おそらくワクチン研究の中で「最有力株」と考えられている、GEN003についてであります☆ Phase 2が現在進行中であることは以前にも報告させて頂きましたが、今回はその中間報告がUPされておりましたので、ご報告をしたいと思います☆♪


（１）GEN003ってナニ？

GEN003については、これまでにもいくつか情報をUPしてまいりました。最新の情報については、こちらをご参照ください。

この情報の中で、私が個人的に「オッ！」と思った点としては、

• 2017年の中ごろ（もうすぐですね！）に結果（Phase 2b）が公表されるだろう
• 2017年末までには Phase 3 が開始されるだろう
• Phase 3 は「バルトレックスとの併用」を想定したものになるだろう

という3点を挙げたのですが、今回の投稿は、この最初の項目に相当するものであります☆

（２）で、その内容はどんなものだったの？

そもそも、Phase 2bは対象となる「新薬の効果を確かめる」ことを目的としており、Phase 2aで見出した適用量などを実際に治験者に投与することで確認するためのものです。もうちょっと詳しく解説しているサイト（こちらから）から引用してみたいと思います。

Phase 2試験は、前期（Phase 2a）と後期（Phase 2b）に分かれます。前期では、いくつかの用量を用いて、薬が有効であるかどうかと、用量を増やすことで効果が強まるか（用量反応があるか）といったことを調べます。用量を増やしても効果が強まらなければ、低い用量を設定した方がよいですし、用量に応じて効果が強まるのであれば、実際に使用する際に用量を調整することで、薬の効果（あるいは安全性）をコントロールできることになります。

臨床試験を実施すると、探索的という単語と検証的という言葉を耳にするかもしれませんが、Phase 2aは、探索的な試験にあたります。探索的試験とは、読んで字のごとく、薬効を探す段階の試験である。一方、Phase 2bは検証的な位置づけのことが多く、Phase 2aから得られたデータをもとに仮説を立て（効果の大きさや用量反応関係など）、その仮説を検証することを目的としています。

まぁ、このように、Phase 2bでは「実際に治験者の協力を得て、新薬の効果を測定する」ことを目的として治験を行うのですが、今回は GEN003が行ったそのPhase 2bの結果について Genosia が公表したものであります。

公表している全文は、最後の方にコピペしておりますので、興味がある方はご覧になるとイイかと思います。今回、特に関係がある部分を抜き出してみましたので、その引用箇所を中心に解説をしていきたいと思います。

About the GEN-003 Phase 2b Clinical Trial
The Phase 2b trial (GEN-003-003) was a randomized, double-blind, placebo-controlled study evaluating potential Phase 3 endpoints with a formulation of GEN-003 manufactured with commercially-scalable processes and expected to be used in future Phase 3 trials. The trial enrolled 131 subjects from 9 institutions in the United States. Subjects were randomized to one of three dose groups - placebo, 60 µg per antigen / 50 µg of adjuvant and 60 µg per antigen / 75 µg of adjuvant - and received three injections at 21-day intervals. Subjects were followed for 12 months after the last dose was administered.

In September 2016, Genocea reported that the trial achieved its primary endpoint, with GEN-003 demonstrating a statistically significant reduction in the rate of viral shedding in the 60 µg per antigen / 50 µg of adjuvant dose group compared to both baseline and placebo. In January 2017, the company reported that the 60 µg per antigen / 50 µg of adjuvant dose of GEN-003 significantly reduced the median genital lesion rate during the six months following dosing compared to placebo. Safety in the trial is continuously reviewed by an independent Drug Monitoring Committee. Throughout the trial, there have been no drug-related serious adverse events or grade 4 reactogenicity and discontinuations due to adverse events have been low and similarly distributed across active dose groups and placebo. A 12-month extension of this study (GEN-003-005) is currently underway to examine the safety, efficacy and durability of a single maintenance dose administered at 12 months after initial dosing.

ここでは、Phase 2b治験についての概要とこれまでに公開した情報について概略が書かれているようです。以下に簡単にまとめてみました。これまでの発表では…、

• Phase 2bでの治験参加者は131名
• 実施場所は、アメリカ国内9カ所
• 治験は以下の3グループに分かれて実施された。ワクチン接種は、21日間隔で計3回投与された。
• GEN003 60μg ＆ 50μg アジュバント（Matrix-M）
• GEN003 60μg ＆ 75μg アジュバント（Matrix-M）
• プラセボ（偽薬）
• 最近の報告結果は以下のとおり。
• 2016年1月発表
• GEN003 60μg ＆ 50μgアジュバントでウィルスの排出を抑える効果アリ
• 2017年1月発表
• 同じ濃度のワクチン試薬で、HSVの発症率を抑えることができた

という内容が公表されていたようなんですが、今回のPhse 2bで明らかになった内容が以下の表に明示されています！

Summary of Reported 12 Month Data 

Endpoint	60/50 (n=43)		60/75 (n=44)		Placebo (n=44)
Number of subjects contributing clinical data	43		44		44
Median genital lesion rate (percent of days with lesions over 12 months)	2.3	%	2.8	%	4.5	%
Percent reduction versus placebo	-49	%	-37	%	NA
p-value versus placebo(1)	0.01		NS		NA
Median number of recurrences over 12 months	1.5		2.0		4.0
Percent reduction versus placebo	-63	%	-50	%	NA
p-value versus placebo(1)	0.01		NS		NA
Median duration of recurrences (days)	2.7		4.0		3.6
Percent reduction versus placebo	-25	%	11	%	NA
p-value versus placebo(1)	0.02		NS		NA
Kaplan-Meier estimate of percent recurrence free after first dose	20	%	16	%	7	%
p-value versus placebo(2)	0.04		NS		NA
Kaplan-Meier estimate of percent recurrence free after last dose	20	%	17	%	8	%
p-value versus placebo(2)	NS		0.05		NA
Number of subjects contributing shedding data	30		32		31
Viral shedding rate reduction from baseline	-42	%	-39	%	-52	%
p-value versus baseline(3)	0.02		NS		0.03
p-value versus placebo (3)	NS		NS		NA

概要は、以下のとおりのようです。

• Median genital lesion rate (percent of days with lesions over 12 months)
  （12か月間でのHSV発症率平均：発症した日数の割合）
• 60/50（43名）　-49％（p<.01）
• 60/50（44名）　-37%（NS 有意差なし）
• Placebo　NA（Not Applicable 該当なし）

• Median number of recurrences over 12 months
  （12か月間での再発回数平均）
• 60/50（43名）　-63％ 1.5回（p<.01）
• 60/50（44名）　-50% 2.0回（NS 有意差なし）
• Placebo　NA 4回（Not Applicable 該当なし）

• Median duration of recurrences (days)
  （再発期間日数平均）
• 60/50（43名）　-25％ 2.7日（p<.01）
• 60/50（44名）　-11% 4.0日（NS 有意差なし）
• Placebo　NA 3.6日（Not Applicable 該当なし）

• Kaplan-Meier estimate of percent recurrence free after first dose
  カプラン・マイヤー推定法による第１回目接種以降の非発症日数の割合
• 60/50（43名）　20％（p<.04）
• 60/50（44名）　16%（NS 有意差なし）
• Placebo　7%（Not Applicable 該当なし）

• Kaplan-Meier estimate of percent recurrence free after last dose
  カプラン・マイヤー推定法による最終接種以降の非発症日数の割合
• 60/50（43名）　20％（NS 有意差なし）
• 60/50（44名）　17%（p<.05）
• Placebo　8%（Not Applicable 該当なし）

• Viral shedding rate reduction from baseline
  比較ベースラインからの排出量の減少
• 60/50（30名）　-42％（NS 有意差なし）
• 60/50（32名）　-39%（NS 有意差なし）
• Placebo（31名）　-52%（Not Applicable 該当なし）

有意差が確認されている項目（下線項目）を見ると、圧倒的に 60/50 の組み合わせが多く、おそらくはこの組み合わせで今後の治験が行われるのでしょうが…、

再発率を約半分に抑えるのは以前から報告があった通りだけど、今回の結果に関してみると、以前は「ウィルスの排出にも効果があった」としていたのに対し、今回の結果では「有意差なし」という結果になっているのは、トッテモ疑問…

 と思ってしまいました… "(-""-)"

だってですよ、これって今まさに起こっている安倍総理の国会審議と同じようなもので…、

　　以前は効果があったと思われるけど、今回はなかったです… ( ˘ω˘ )

ということですからね…。最終的には、「ウィルスの排出に関しては、投与される人の体質による」ということになるのかもしれません…。

そうなると、「じゃぁ、誰に効果があって、誰に対して効果が無いの？」という話になると思うんですね。もちろん、まだそこまで進んでいるわけではないと思いますが、やはり、前回の投稿で紹介したインタビューにあったように…、

　　GEN003に関しては、既存のヘルペス薬との併用で進められる

ということになるかと思います。(^_-)-☆



■■■■■■■■■■■■■■■■■■■■■■■■■■


今回は、GEN003の最新情報をお届けしましたが、如何だったでしょうか？

GEN003に関しては、以前の投稿でも紹介しておりましたが、「バルトレックスなどの既存薬との併用で進められる」ことになるかと思います。ただ、これでもかなりの進歩になるわけでして…、これまで全く認められてこなかった単純ヘルペス用ワクチンが認められる可能性が高くなるのであれば…、

　　かなり大きな前進！(^^)/

として考えることが出来るでしょう！

少しずつではありますが、ワクチン研究も前進していることは確かです。発見された当初は「不治の病」と恐れられていたHIVも、薬の発展により、感染者であっても普通の生活ができるようになってきている、と言われています。

大丈夫！

と信じて、一日一日を大切に生きてまいりましょう☆

また、次回の投稿でお会いしましょう☆(^^♪

Genocea Reports Positive Top-Line 12-Month Phase 2b Data for GEN-003 in Genital Herpes

http://ir.genocea.com/releasedetail.cfm?ReleaseID=1034082 

• Statistically significant result on expected Phase 3 primary endpoint with Phase 3 dose -
• Positive results on multiple secondary clinical endpoints -
• Potentially the first new treatment in more than 20 years for the millions infected with genital herpes -
• Conference call today at 8 a.m. ET -

CAMBRIDGE, Mass., July 24, 2017 (GLOBE NEWSWIRE)

Genocea Biosciences, Inc. (NASDAQ:GNCA), a biopharmaceutical company developing novel vaccines and immunotherapies targeting T cell antigens, announced today positive 12-month top-line data from the Phase 2b clinical trial for GEN-003, its immunotherapy candidate for patients with genital herpes.

In this 131-subject Phase 2b clinical trial, GEN-003 reduced the median genital lesion rate (or percent days with genital lesions) versus placebo by 49 percent (p=0.01) over the 12 months' post dosing at the 60 µg per antigen / 50 µg of adjuvant dose. Importantly, these results were achieved at the Phase 3 dose and expected Phase 3 primary endpoint. Other clinical endpoints for this dose improved or were consistent with previously reported positive data. No changes were observed to the previously established safety profile of GEN-003.

Chip Clark, President and CEO of Genocea, commented: "We believe these data further solidify the strong clinical profile for GEN-003, which could provide durable, convenient efficacy to a large and, we believe, highly dissatisfied patient population and serve as a cornerstone treatment of this burdensome disease."

"These data and the continued progress of GEN-003 show the potential of this immunotherapy to change the treatment paradigm for patients with genital herpes infections," said Jonathan Temte, M.D., Ph.D., M.S., former chair of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP). "The benefits of using a periodic immunization to achieve fewer and shorter genital herpes outbreaks without the compliance challenges of a daily pill burden would represent an extremely important alternative for patients with genital herpes. I believe the potential individual and societal benefits of a treatment such as GEN-003 to address the uncontrolled growth in genital herpes infections resonates with the goals of bodies such as the ACIP."

Conference Call
Genocea management will host a conference call and webcast today at 8 a.m. ET to review these data. The conference call may be accessed by dialing (844) 826-0619 for domestic participants and (315) 625-6883 for international callers (reference conference ID 60267894). A live webcast of the conference call will be available online from the investor relations section of the Company's website at http://ir.genocea.com. A webcast replay of the conference call will be available on the Genocea website beginning approximately two hours after the event, and will be archived for 30 days.

About the GEN-003 Phase 2b Clinical Trial
The Phase 2b trial (GEN-003-003) was a randomized, double-blind, placebo-controlled study evaluating potential Phase 3 endpoints with a formulation of GEN-003 manufactured with commercially-scalable processes and expected to be used in future Phase 3 trials. The trial enrolled 131 subjects from 9 institutions in the United States. Subjects were randomized to one of three dose groups - placebo, 60 µg per antigen / 50 µg of adjuvant and 60 µg per antigen / 75 µg of adjuvant - and received three injections at 21-day intervals. Subjects were followed for 12 months after the last dose was administered.

In September 2016, Genocea reported that the trial achieved its primary endpoint, with GEN-003 demonstrating a statistically significant reduction in the rate of viral shedding in the 60 µg per antigen / 50 µg of adjuvant dose group compared to both baseline and placebo. In January 2017, the company reported that the 60 µg per antigen / 50 µg of adjuvant dose of GEN-003 significantly reduced the median genital lesion rate during the six months following dosing compared to placebo. Safety in the trial is continuously reviewed by an independent Drug Monitoring Committee. Throughout the trial, there have been no drug-related serious adverse events or grade 4 reactogenicity and discontinuations due to adverse events have been low and similarly distributed across active dose groups and placebo. A 12-month extension of this study (GEN-003-005) is currently underway to examine the safety, efficacy and durability of a single maintenance dose administered at 12 months after initial dosing.

Summary of Reported 12 Month Data 

Endpoint	60/50 (n=43)		60/75 (n=44)		Placebo (n=44)
Number of subjects contributing clinical data	43		44		44
Median genital lesion rate (percent of days with lesions over 12 months)	2.3	%	2.8	%	4.5	%
Percent reduction versus placebo	-49	%	-37	%	NA
p-value versus placebo(1)	0.01		NS		NA
Median number of recurrences over 12 months	1.5		2.0		4.0
Percent reduction versus placebo	-63	%	-50	%	NA
p-value versus placebo(1)	0.01		NS		NA
Median duration of recurrences (days)	2.7		4.0		3.6
Percent reduction versus placebo	-25	%	11	%	NA
p-value versus placebo(1)	0.02		NS		NA
Kaplan-Meier estimate of percent recurrence free after first dose	20	%	16	%	7	%
p-value versus placebo(2)	0.04		NS		NA
Kaplan-Meier estimate of percent recurrence free after last dose	20	%	17	%	8	%
p-value versus placebo(2)	NS		0.05		NA
Number of subjects contributing shedding data	30		32		31
Viral shedding rate reduction from baseline	-42	%	-39	%	-52	%
p-value versus baseline(3)	0.02		NS		0.03
p-value versus placebo (3)	NS		NS		NA

Statistical tests pre-specified in Phase 2b trial protocol as follows:
(1) Wilcoxon Rank Sum test
(2) Log rank test
(3) Poisson mixed effect model with empirical variance
NS = p > 0.05

About GEN-003
Inducing a T cell response against genital herpes is critical to treating the clinical symptoms of disease and controlling transmission of the infection. GEN-003 is a first-in-class investigational T cell-directed immunotherapy designed to elicit both a T cell and B cell (antibody) immune response. The immunotherapy was designed using Genocea's ATLAS™ platform, which profiles the comprehensive spectrum of actual T cell responses mounted by humans in response to disease and identifies antigen targets that drive effective T cell responses. GEN-003 includes the antigens ICP4 and gD2 along with Matrix-M™ adjuvant (licensed from Novavax, Inc. (NASDAQ:NVAX)). For more information about GEN-003, please visit the GEN-003 section of the Genocea website.

About Genital Herpes
Genital Herpes affects more than 400 million people worldwide and causes recurrent, painful genital lesions. It can be transmitted to sexual partners, even when the disease is asymptomatic. Current genital herpes therapies only partially control clinical symptoms and viral shedding, a process which drives disease transmission. Incomplete control of genital lesions and transmission risk, expense and the perceived inconvenience of taking a daily medication are hurdles for long-term disease management. Immunity through T cells is believed to be particularly critical to the control and possible prevention of genital herpes infections.

About Genocea Biosciences, Inc.
Genocea is harnessing the power of T cell immunity to develop life-changing vaccines and immunotherapies. While traditional immunotherapy discovery methods have largely used predictive methods to propose T cell targets, or antigens, Genocea has successfully developed ATLAS™, its proprietary technology platform, to identify clinically relevant antigens of T cells based on actual human immune responses. Genocea used ATLAS to identify the antigens in its lead clinical candidate, GEN-003, an investigational immunotherapy to treat genital herpes, and is currently using ATLAS in immuno-oncology applications to develop neoantigen cancer vaccines (with an IND filing expected by the end of 2017), general cancer vaccines and a vaccine targeting cancers caused by Epstein-Barr Virus. For more information, please visit www.genocea.com.

About Matrix-M
Matrix-M™ is a next-generation, patented saponin-based adjuvant comprised of purified saponin fractions mixed with synthetic cholesterol and a phospholipid to form stable particles than can be readily formulated with a variety of vaccine antigens. Saponin-based adjuvants act in part by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in the local lymph nodes. Thus, Matrix-M™ induces both a cell-mediated and antibody mediated immune response.  Matrix-M is manufactured by Novavax, Inc (NASDAQ:NVAX), in Uppsala Sweden.

Forward-Looking Statements
Statements herein relating to future business performance, conditions or strategies and other financial and business matters, including expectations regarding clinical developments, are forward-looking statements within the meaning of the Private Securities Litigation Reform Act. Genocea cautions that these forward-looking statements are subject to numerous assumptions, risks, and uncertainties that change over time. Factors that may cause actual results to differ materially from the results discussed in the forward-looking statements or historical experience include risks and uncertainties, including Genocea's ability to progress any product candidates in preclinical or clinical trials; the ability of ATLAS to identify promising oncology vaccine and immunotherapy product candidates; the scope, rate and progress of its preclinical studies and clinical trials and other research and development activities; anticipated clinical trial results; anticipated timing for initiation of new clinical trials; current results may not be predictive of future results; even if the data from preclinical studies or clinical trials is positive, regulatory authorities may require additional studies for approval and the product may not prove to be safe and efficacious; Genocea's ability to enter into future collaborations with industry partners and the government and the terms, timing and success of any such collaboration; risks associated with the manufacture and supply of clinical and commercial product; the cost of filing, prosecuting, defending and enforcing any patent claims and other intellectual property rights; Genocea's ability to obtain rights to technology; competition for clinical resources and patient enrollment from drug candidates in development by other companies with greater resources and visibility; the rate of cash utilized by Genocea in its business and the period for which existing cash will be able to fund such operation; Genocea's ability to obtain adequate financing in the future to continue its clinical programs through product licensing, co-promotional arrangements, public or private equity or debt financing or otherwise; general business conditions; competition; business abilities and judgment of personnel; the availability of qualified personnel and other factors set forth under "Risk Factors" in Genocea's Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and other filings with the Securities and Exchange Commission (the "SEC"). Further information on the factors and risks that could affect Genocea's business, financial conditions, and results of operations is contained in Genocea's filings with the SEC, which are available at www.sec.gov. These forward-looking statements speak only as of the date of this press release and Genocea assumes no duty to update forward-looking statements.

For media:
Jennifer LaVin
207-360-0473
jennifer.lavin@genocea.com

For investors:
Jonathan Poole
617-876-8191
jonathan.poole@genocea.com