Regulatory Open Forum

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline
------------------------------

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze

Bs-mAb is a special class of mAb therapeutics engineered mostly to be artificial not natural. While it has common elements of a typical mAb drug, the MOA may be harder to predict in the clinical setting than that of a mAb drug. Thanks to a vast amount of knowledges and experience gained by the industry and regulators alike over last 15-20 years, a mAb drug is rarely known to have some safety concern to enter phase I nowadays. But Bs-mAb may be a different beast to watch out due to its unique engineered nature of the structure which may cause some unintended clinical consequence in human. Non-clinical studies, if a relevant model is available, are more desirable to test it out first to increase the confidence of its safety to enter in phase I. However, if no relevant model is available, the clinical protocol should be well crafted to gradually expose the human subjects in some kind of stepwise escalating fashion unlike a typical mAb drug. Welcome others to join the discussion and can share some of the stories recently in the news or in the past.

------------------------------
Jingdong Zhu
Independent Consultant
Basking Ridge NJ
USA
------------------------------

Original Message:
Sent: 05-May-2021 12:35
From: Narayan Rao
Subject: Development of bispecific antibodies

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze

Dear Jingdong Zhu,
Thank you very much for sharing your thoughts and comments!
Of course, I totally agree with you that FIH clinical trial protocol needs to consider and address all uncertainties as much as possible. However, I don't like stepwise dose escalation in single (if I understood your idea correctly) patient - it seems misleading. It makes assessment of safety / immunogenicity difficult. Moreover, in oncology clinical trials, where cancer patients participate in phase I clinical trial, dose titration will complicate efficacy evaluation as well.
Kind regards,
Shorena

------------------------------
Shorena Archuadze
Tbilisi
Georgia
------------------------------

Original Message:
Sent: 07-May-2021 00:19
From: Jingdong Zhu
Subject: Development of bispecific antibodies

Bs-mAb is a special class of mAb therapeutics engineered mostly to be artificial not natural. While it has common elements of a typical mAb drug, the MOA may be harder to predict in the clinical setting than that of a mAb drug. Thanks to a vast amount of knowledges and experience gained by the industry and regulators alike over last 15-20 years, a mAb drug is rarely known to have some safety concern to enter phase I nowadays. But Bs-mAb may be a different beast to watch out due to its unique engineered nature of the structure which may cause some unintended clinical consequence in human. Non-clinical studies, if a relevant model is available, are more desirable to test it out first to increase the confidence of its safety to enter in phase I. However, if no relevant model is available, the clinical protocol should be well crafted to gradually expose the human subjects in some kind of stepwise escalating fashion unlike a typical mAb drug. Welcome others to join the discussion and can share some of the stories recently in the news or in the past.

------------------------------
Jingdong Zhu
Independent Consultant
Basking Ridge NJ
USA

Original Message:
Sent: 05-May-2021 12:35
From: Narayan Rao
Subject: Development of bispecific antibodies

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze

Original Message:
Sent: 5/9/2021 2:31:00 PM
From: Shorena Archuadze
Subject: RE: Development of bispecific antibodies

Dear Jingdong Zhu,
Thank you very much for sharing your thoughts and comments!
Of course, I totally agree with you that FIH clinical trial protocol needs to consider and address all uncertainties as much as possible. However, I don't like stepwise dose escalation in single (if I understood your idea correctly) patient - it seems misleading. It makes assessment of safety / immunogenicity difficult. Moreover, in oncology clinical trials, where cancer patients participate in phase I clinical trial, dose titration will complicate efficacy evaluation as well.
Kind regards,
Shorena

------------------------------
Shorena Archuadze
Tbilisi
Georgia
------------------------------

Original Message:
Sent: 07-May-2021 00:19
From: Jingdong Zhu
Subject: Development of bispecific antibodies

Bs-mAb is a special class of mAb therapeutics engineered mostly to be artificial not natural. While it has common elements of a typical mAb drug, the MOA may be harder to predict in the clinical setting than that of a mAb drug. Thanks to a vast amount of knowledges and experience gained by the industry and regulators alike over last 15-20 years, a mAb drug is rarely known to have some safety concern to enter phase I nowadays. But Bs-mAb may be a different beast to watch out due to its unique engineered nature of the structure which may cause some unintended clinical consequence in human. Non-clinical studies, if a relevant model is available, are more desirable to test it out first to increase the confidence of its safety to enter in phase I. However, if no relevant model is available, the clinical protocol should be well crafted to gradually expose the human subjects in some kind of stepwise escalating fashion unlike a typical mAb drug. Welcome others to join the discussion and can share some of the stories recently in the news or in the past.

------------------------------
Jingdong Zhu
Independent Consultant
Basking Ridge NJ
USA

Original Message:
Sent: 05-May-2021 12:35
From: Narayan Rao
Subject: Development of bispecific antibodies

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze

Dear Jingdong Zhu,

Thank you for clarification!!
I appreciate your comments!
Kind regards,
Shorena

------------------------------
Shorena Archuadze
Tbilisi
Georgia
------------------------------

Original Message:
Sent: 09-May-2021 14:55
From: Jingdong Zhu
Subject: Development of bispecific antibodies

Hi Shoreba,

I think my suggestion refers to dose escalation with different human subjects and pause and evaluate before next higher dose again on other subjects. However, the details cannot be crafted without further information and as I said it needs to be carefully crafted. It is very difficult to discuss the details. The key point was bs-Ab, unlike MAb, present specific challenges and it should not be drawing an analogy to MAb.

Sent from my iPhone

Original Message:
Sent: 5/9/2021 2:31:00 PM
From: Shorena Archuadze
Subject: RE: Development of bispecific antibodies

Dear Jingdong Zhu,
Thank you very much for sharing your thoughts and comments!
Of course, I totally agree with you that FIH clinical trial protocol needs to consider and address all uncertainties as much as possible. However, I don't like stepwise dose escalation in single (if I understood your idea correctly) patient - it seems misleading. It makes assessment of safety / immunogenicity difficult. Moreover, in oncology clinical trials, where cancer patients participate in phase I clinical trial, dose titration will complicate efficacy evaluation as well.
Kind regards,
Shorena

------------------------------
Shorena Archuadze
Tbilisi
Georgia

Original Message:
Sent: 07-May-2021 00:19
From: Jingdong Zhu
Subject: Development of bispecific antibodies

Bs-mAb is a special class of mAb therapeutics engineered mostly to be artificial not natural. While it has common elements of a typical mAb drug, the MOA may be harder to predict in the clinical setting than that of a mAb drug. Thanks to a vast amount of knowledges and experience gained by the industry and regulators alike over last 15-20 years, a mAb drug is rarely known to have some safety concern to enter phase I nowadays. But Bs-mAb may be a different beast to watch out due to its unique engineered nature of the structure which may cause some unintended clinical consequence in human. Non-clinical studies, if a relevant model is available, are more desirable to test it out first to increase the confidence of its safety to enter in phase I. However, if no relevant model is available, the clinical protocol should be well crafted to gradually expose the human subjects in some kind of stepwise escalating fashion unlike a typical mAb drug. Welcome others to join the discussion and can share some of the stories recently in the news or in the past.

------------------------------
Jingdong Zhu
Independent Consultant
Basking Ridge NJ
USA

Original Message:
Sent: 05-May-2021 12:35
From: Narayan Rao
Subject: Development of bispecific antibodies

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze

Dear Narayan Rao,
Thank you very much for your comments!
They are definitely helpful!
Kind regards,
Shorena

------------------------------
Shorena Archuadze
Tbilisi
Georgia
------------------------------

Original Message:
Sent: 05-May-2021 12:35
From: Narayan Rao
Subject: Development of bispecific antibodies

Bispecific MaBs development are very much similar to mono specific Mab! The area you may need to focus however on bispecific is to characterize the following not just for regulatory purpose but also for your own interest so that your advanced development program can be rationally constructed/developed:

"In vitro and in vivo pharmacology studies may also offer the opportunity to generate nonclinical
data supporting the scientific rationale of the bispecific antibody (e.g., showing that blocking two
 targets yields additive or synergistic efficacy compared to a monospecific comparator; showing
that simultaneous cross-linking of two receptors offers efficacy that cannot be achieved with a
monospecific product; for agonistic products, showing expected activation of the immune
system). These studies could also be used to select the first-in-human (FIH) dose."

The other point Id like to emphasize is that response/MOA in nonclinical studies may not translate into clinical findings that doesn't mean its a requirement to exactly match the performance! You can still get approved based on clinical efficacy studies as long as the safety is ensured!

Hope this helps!

------------------------------
GRSAOnline

Original Message:
Sent: 04-May-2021 16:16
From: Shorena Archuadze
Subject: Development of bispecific antibodies

Hello,

I've lately started working on non-clinical and clinical development of bispecific antibodies (BsAbs).

Unfortunately I could not find any regulatory guidances on the development of BsAbs.

The draft Guidance for Industry from FDA was issued in April 2019. Unfortunately, I failed to find the finalized guidance.

I would appreciate your thoughts and recommendations on if:

- the final version of the "Bispecific Antibody development programs" Guidance of industry is available?

- Are there any available regulatory guidelines / recommendations?

Thank you in advance!

Kind regards,

Shorena Archuadze