GKOS

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 10

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 637

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $29.48 to $30.47 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 9

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 66,790

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $29.48 to $30.47 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 14

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 0

F7 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.49 to $32.46 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 13

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 0

F7 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.49 to $32.46 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 12

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 445

F6 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $30.48 to $31.47 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 11

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 46,676

F6 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $30.48 to $31.47 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 10

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 637

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $29.48 to $30.47 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 9

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 66,790

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $29.48 to $30.47 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 8

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 1,523

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.64 to $33.39 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 7

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 159,798

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.64 to $33.39 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 6

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 2,291

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.64 to $32.62 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 5

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 240,314

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.64 to $32.62 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 8

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 1,523

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.64 to $33.39 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 7

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 159,798

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.64 to $33.39 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 6

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 2,291

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.64 to $32.62 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 5

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 240,314

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $31.64 to $32.62 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 4

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 3,511

F2 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.42 to $33.40 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 3

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 368,406

F2 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.42 to $33.40 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 2

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 5,362

F1 · price: The price reported in Column 4 is a weighted average price. These shares of the Issuer's common stock ("Shares") were sold in multiple transactions at prices ranging from $31.41 to $32.39 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the Securities and Exchange Commission (the "SEC") full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000220 · ss82779_4.xml · nonDerivative · entry 1

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 562,839

F1 · price: The price reported in Column 4 is a weighted average price. These shares of the Issuer's common stock ("Shares") were sold in multiple transactions at prices ranging from $31.41 to $32.39 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the Securities and Exchange Commission (the "SEC") full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III.

F10 · ownership.nature: Samuel D. Isaly, who was included as a Reporting Person on previous reports under Section 16 of the Exchange Act filed by GP III and Advisors, is no longer subject to Section 16 with respect to securities of the Issuer.

F11 · ownership.nature: This report on Form 4 is jointly filed by GP III and Advisors. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 4

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 3,511

F2 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.42 to $33.40 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 3

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 368,406

F2 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $32.42 to $33.40 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 2

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 5,362

F1 · price: The price reported in Column 4 is a weighted average price. These shares of the Issuer's common stock ("Shares") were sold in multiple transactions at prices ranging from $31.41 to $32.39 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the Securities and Exchange Commission (the "SEC") full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F9 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. By virtue of such relationships, Advisors may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities. Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by Associates III.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-18-000221 · ss82780_4.xml · nonDerivative · entry 1

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 562,839

F1 · price: The price reported in Column 4 is a weighted average price. These shares of the Issuer's common stock ("Shares") were sold in multiple transactions at prices ranging from $31.41 to $32.39 inclusive. Upon request, the Reporting Person undertakes to provide the Issuer, any security holder of the Issuer, or the Securities and Exchange Commission (the "SEC") full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F8 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors"), a registered adviser under the Investment Advisors Act of 1940, as amended, is the managing member of GP III. By virtue of such relationships, GP III and Advisors may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to beneficially own such securities for purposes of Rule 13d-3 under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). Advisors exercised this investment and voting power through a management committee comprised of Carl L. Gordon, Sven H. Borho and Jonathan T. Silverstein, each of whom disclaims beneficial ownership of the Shares held by OPI III. The Reporting Person is a member of Advisors.

F10 · ownership.nature: Each of the Reporting Person, GP III and Advisors disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) of the Exchange Act, except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0001562180-18-000491 · primarydocument.xml · derivative · entry 6

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 0

Underlying: Common Stock · 47,000 shares

Expires 2018-01-29

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

F1 · derivative.exercise_date: This option was granted on January 29, 2008, has a four-year vesting schedule in which 25% vested on the first year anniversary date of the grant and the remainder vested in equal monthly installments for 36 months thereafter, such that the stock option vests in full on the four-year anniversary of the grant date.

SEC source: 0001562180-18-000491 · primarydocument.xml · nonDerivative · entry 1

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Indirect · Through the Burns Family Trust

Disclosed balance after: 277,240

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

SEC source: 0001562180-18-000210 · primarydocument.xml · nonDerivative · entry 1

Hoffmeister David F · CIK 0001305975 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 2,123

F1 · security: Represents a grant of restricted stock units received by the reporting person in lieu of annual director retainer fees pursuant to a stock-for-fees election under the Issuer's Director Compensation Policy. The units will vest in full on the one-year anniversary of the grant date and are payable in an equivalent number of shares of the Issuer's common stock.

F2 · balance_after: Consists of 2,123 restricted stock units that have not yet vested or been delivered to the Reporting Person.

SEC source: 0001562180-18-000212 · primarydocument.xml · nonDerivative · entry 1

Stapley Marc · CIK 0001539796 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 2,548

F1 · security: Represents a grant of restricted stock units received by the reporting person in lieu of annual director retainer fees pursuant to a stock-for-fees election under the Issuer's Director Compensation Policy. The units will vest in full on the one-year anniversary of the grant date and are payable in an equivalent number of shares of the Issuer's common stock.

F2 · balance_after: Consists of 2,548 restricted stock units that have not yet vested or been delivered to the Reporting Person.

SEC source: 0001562180-17-004038 · primarydocument.xml · derivative · entry 6

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 47,000

Underlying: Common Stock · 20,000 shares

Expires 2018-01-29

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

F1 · derivative.exercise_date: This option was granted on January 29, 2008, has a four-year vesting schedule in which 25% vested on the first year anniversary date of the grant and the remainder vested equally for 36 months thereafter, such that the stock option vests in full on the four-year anniversary of the grant date.

SEC source: 0001562180-17-004038 · primarydocument.xml · nonDerivative · entry 1

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Indirect · Through the Burns Family Trust

Disclosed balance after: 230,240

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

SEC source: 0001562180-17-003884 · primarydocument.xml · derivative · entry 1

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003882 · primarydocument.xml · derivative · entry 1

Hoffmeister David F · CIK 0001305975 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003883 · primarydocument.xml · derivative · entry 1

Kliman Gilbert H · CIK 0001293171 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003881 · primarydocument.xml · derivative · entry 1

LINK WILLIAM J PHD · CIK 0001228684 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003886 · primarydocument.xml · derivative · entry 1

WEISNER AIMEE S · CIK 0001227308 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003885 · primarydocument.xml · derivative · entry 1

Stapley Marc · CIK 0001539796 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003880 · primarydocument.xml · derivative · entry 1

Foley Mark J · CIK 0001529196 · Director

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 15,000

Underlying: Common Stock · 15,000 shares

Expires 2027-12-13

F1 · derivative.exercise_date: Granted pursuant to the Issuer's 2015 Omnibus Incentive Compensation Plan. Vests in full on May 31, 2018.

SEC source: 0001562180-17-003676 · primarydocument.xml · nonDerivative · entry 1

Gilliam Joseph E · CIK 0001705850 · CFO, SVP Corporate Development

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 102,100

F1 · price: This transaction was executed in multiple trades at prices ranging from $23.835 to $23.85. The price reported above reflects the weighted average price. The reporting person hereby undertakes to provide upon request to the SEC staff, the issuer or a security holder of the issuer full information regarding the number of shares and prices at which the transaction was effected.

SEC source: 0001562180-17-002920 · primarydocument.xml · derivative · entry 9

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 120,640

Underlying: Common Stock · 48,788 shares

Expires 2020-01-26

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

F4 · derivative.exercise_date: This option was granted on January 26, 2010, has a four-year vesting schedule in which 25% vested on the first year anniversary date of the grant and the remainder vested equally for 36 months thereafter, such that the stock option vests in full on the four-year anniversary of the grant date.

SEC source: 0001562180-17-002920 · primarydocument.xml · derivative · entry 8

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Direct

Disclosed balance after: 67,000

Underlying: Common Stock · 25,000 shares

Expires 2018-01-29

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

F3 · derivative.exercise_date: This option was granted on January 29, 2008, has a four-year vesting schedule in which 25% vested on the first year anniversary date of the grant and the remainder vested equally for 36 months thereafter, such that the stock option vests in full on the four-year anniversary of the grant date.

SEC source: 0001562180-17-002920 · primarydocument.xml · nonDerivative · entry 3

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Indirect · Through the Burns Family Trust

Disclosed balance after: 210,240

F1 · kind: These trades were made pursuant to a Rule 10b5-1 trading plan with pre-determined share amounts and prices.

F2 · price: This transaction was executed in multiple trades at prices ranging from $41.25 to $42.07. The price reported above reflects the weighted average price. The reporting person hereby undertakes to provide upon request to the SEC staff, the issuer or a security holder of the issuer full information regarding the number of shares and prices at which the transaction was effected.

SEC source: 0001562180-17-002920 · primarydocument.xml · nonDerivative · entry 2

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Indirect · Through the Burns Family Trust

Disclosed balance after: 284,028

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

SEC source: 0001562180-17-002920 · primarydocument.xml · nonDerivative · entry 1

Burns Thomas William · CIK 0001644557 · Director · Chief Executive Officer

10b5-1 filing: Not disclosed

Ownership: Indirect · Through the Burns Family Trust

Disclosed balance after: 235,240

Exercise/conversion can include RSU settlement. Transaction price and option strike are different fields; a missing price is not zero. Derivative and underlying rows can describe the same event.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 10

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 7,895

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $40.33 to $41.22 inclusive. Upon request, the Reporting Person undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F7 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. Isaly is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, Advisors and Isaly may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 9

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 828,605

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $40.33 to $41.22 inclusive. Upon request, the Reporting Person undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F6 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors") is the managing member of GP III. Samuel D. Isaly ("Isaly"), a natural person, is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, GP III, Advisors and Isaly may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 8

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 8,448

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $39.33 to $40.30 inclusive. Upon request, the Reporting Person undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F7 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. Isaly is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, Advisors and Isaly may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 7

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 886,652

F4 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $39.33 to $40.30 inclusive. Upon request, the Reporting Person undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F6 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors") is the managing member of GP III. Samuel D. Isaly ("Isaly"), a natural person, is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, GP III, Advisors and Isaly may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 6

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 10,256

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $37.75 to $38.04 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F7 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III"). Advisors is the general partner of Associates III. Isaly is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, Advisors and Isaly may be deemed to have voting and investment power over the securities held by Associates III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000698 · ss57834_4.xml · nonDerivative · entry 5

ORBIMED ADVISORS LLC · CIK 0001055951 · Director

OrbiMed Capital GP III LLC · CIK 0001432241 · Director

ISALY SAMUEL D · CIK 0001055949 · Director

Joint disclosure: these amounts are not allocated separately to each reporting owner.

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 1,076,444

F3 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $37.75 to $38.04 inclusive. Upon request, the Reporting Persons undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F6 · ownership.nature: These Shares are held of record by OrbiMed Private Investments III, LP ("OPI III"). OrbiMed Capital GP III LLC ("GP III") is the general partner of OPI III, and OrbiMed Advisors LLC ("Advisors") is the managing member of GP III. Samuel D. Isaly ("Isaly"), a natural person, is the managing member of and owner of a controlling interest in Advisors. By virtue of such relationships, GP III, Advisors and Isaly may be deemed to have voting and investment power over the securities held by OPI III and as a result may be deemed to have beneficial ownership over such securities.

F8 · ownership.nature: This report on Form 4 is jointly filed by GP III, Advisors, and Isaly. Each of the Reporting Persons disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. The Reporting Persons have designated a representative, currently Jonathan T. Silverstein, a member of Advisors, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any of the Reporting Persons is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.

SEC source: 0000947871-17-000697 · ss57835_4.xml · nonDerivative · entry 10

SILVERSTEIN JONATHAN · CIK 0001171005 · Director

10b5-1 filing: Not disclosed

Ownership: Indirect · See Footnotes

Disclosed balance after: 7,895

F5 · price: The price reported in Column 4 is a weighted average price. These Shares were sold in multiple transactions at prices ranging from $40.33 to $41.22 inclusive. Upon request, the Reporting Person undertake to provide the Issuer, any security holder of the Issuer, or the SEC full information regarding the Shares sold at each separate price within the range set forth in this footnote.

F7 · ownership.nature: These Shares are held of record by OrbiMed Associates III, LP ("Associates III") and may be deemed to be indirectly beneficially owned by Advisors and Isaly. Advisors is the sole general partner of Associates III. Isaly is the managing member of, and holder of a controlling interest in, Advisors. By virtue of such relationships, Advisors and Isaly may be deemed to have voting and investment power with respect to the securities held by Associates III noted above. As a result, each of Advisors and Isaly may be deemed to have beneficial ownership of the securities held by Associates III.

F8 · ownership.nature: Each of the Reporting Person, GP III, Advisors, and Isaly disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of its or his pecuniary interest therein, if any. This report shall not be deemed an admission that any such entity or person, including the Reporting Person, is a beneficial owner of such securities for the purpose of Section 16 of the Exchange Act, or for any other purpose.