Project Evaluation Report ofSectoral Monitoring Committee

1. Project Title:DRUG DISCOVERY: BUGS TO DRUGS PROGRAM (BSC0211)

2. Project Details:

Nodal lab CSIR-IMTECH

Participating CSIR-IMTECH Labs

Nodal Dr. Ravinder S. Jolly, Chief Scientist, CSIR-IMTECH, Sec 39A, Officer Chandigarh-036

Dr. Hemraj Nandanwar*, Principal Scientist, CSIR-IMTECH, Sec 39A, Chandigarh -036

Taskforce Director, CSIR-IMTECH Chairman

Total Man 1890 Days

Approved 1743.00 Lakhs Cost

Fund 1435.50 Lakhs received

Fund 1034.50 Lakhs as on March 2016 utilized

3. Periodic Key Recommendations of Task Force/RC/Monitoring Committee

S.N Key Action taken on Proposed Revised o. Recommendatio Key Deliverables Deliverable

ns of Task Recommendatio (approved Force/RC/Monito ns by Task ring Committee Force)

1. 40th RC April 20- RCwas No deliverables to None 21, 2012: Project appraised about mention in this period was in the submission of as it was in conceiving submission stage. project, exercise stage.

for which started But the proposed in May 2010 deliverables Not any technical comprehensively in recommendations the project were:

• Well established targets for cancer, Mtb, etc. as inhibitor of ribonucleotidereduc tase, perpxisome proliferator

activated receptors PRARs, Nf-KB,

• lmmunomodulator

• lmmunosupressant for other therapeutic applications

• Inhibitors of Mtb biofilm,

• Inhibitor of Candida! biofilms,

• Antimalarials,

• Adjuvants/potentiat or of Tb drugs such as efflux pump inhibitors

2. 41st RC Dec 10- Sanction of Based on the above None 11, 2012: Project project was deliverables was in initial received in Sept

• Advanced lead stage 2012 with generation - 15

expenditure outlay of Rs. • Identification of

17.43 clinical

Candidates/NCE -3 to 5

• Patent Applications -5 to 6

• PhDs- 10& Publications

3. 42nd RC Nov 22- RC's suggestion Relief from Secondary None 23, 2013: RC for CAE effect on iron overload found the blood progress to be haemoglobin was very good. RC amended. suggested to look for the effect of caerulomycin (CAE) on the blood haemoglobin since the CAE acts as a iron chelator

4. 43rd RC May 29- --- --- None 30, 2014: RC considered the report and found the proQress to be

very good. No additional recommendations

5. 44th RC Dec 20- --- --- None 21, 2014: RC found the progress to be very good. No additional recommendations

6. 46th RC Jan 16, RC verbally --- None 2016 Minutes are appreciated the not circulated so efforts made by far the team

4. Project Achievements:

Proposed Achieved If not Deliverables Deliverables achieved,

reasons thereof

Advanced lead Leads Generated: 20 (in addition 2 new generation - 15 screens developed)

• Immunosuppressant for organ transplant -4

• Secondary iron overload - 3

• Arthritis - 1

• lmmunomodulator using TDB/NOD2L to decrease the dose and duration of TB drug regime - 1

• Efflux pump inhibitor (EPI) as adjuvant -1

• nosocomial and hospital infections by MDR Gram negative bacteria - 2

• New drug which will be cleaner (even if less potent), may be of immense use in Tuberculosis endemic regions. - 1

• Novel non-lactam inhibitors of ~-lactamase for treatment and diagnosis of Mycobacterium Tuberculosis - 1

• specific antitubercular activity, could kill Mtb cells at sub-micromolar concentrations - 2

• Antimalarials - 2

• F-actin depolymerizing activity - 2 New screens Developed - 2

• NewHTS method against a-synuclein toxicity, one of the important tar-g_et in

neurodegenerative disorders

• A platforms for in vitro and in vivo testing of various preparations (extracts/fractions/compounds) for antimalarial activity

Identification of Candidates identified - 3 (May add one more clinical soon) Candidates/NCE - 3 • Organ Transplant (with back up to 5 molecules)

• Secondary iron overload (with back up molecules)

• Arthritis No NCE filed yet (need more data)

5. Outcomesand outputs from the projects:

a. Outcomes

1. Lead(s) identified : Number and names with TRL

s .No.

I.

II.

Ill.

IV.

Technology Lead identified

Immunosuppressant for use in organ transplant (main molecule with 2 backups)

Therapeutic and preventive treatment of secondary iron overload (main molecule with 2 backups)

Immunosuppressant for use in organ transplant and arthritis

TDB/NOD-2 ligand, immunomodulation to decrease the dose and duration of TB drugs regime (immunotherapy)

Salient features

The molecule is expected to be devoid of some of the toxicity issues of currently used drugs in clinic. Moreover, our molecule is expected to considerably lower the cost of therapy.

Relief from secondary iron overload: huge societal and economic value for the product is expected. Currently, only one (or two) drugs have been approved by FDA for the purpose, leaving excellent potential for developing newer molecules

Caerulomycin A as an immunosuppressant to treat arthritis and delay of organ transplants by generating regulatory T cells (Tregs).

Use of molecules of innate immunity is gaining momentum as a novel therapy to modulate the immune system against the pathogens

Cur.T RL

TRL5

TRL4

TRL4

TRL2

V.

VI.

VII.

Efflux pump inhibitor (EPI) isolated from microbial source as adjuvant to treat TB as well as other infections caused by Gram positive MDR bacteria

Polymyxin variant (A 1, A2) as solution to treat nosocomial and hospital infections by MDR Gram negative bacteria and its microbial process for production

The process of drug design and testing against few select NRs.

A cleaner and patient friendly anti-Tb drug (even if less potent) and may be of immense Tuberculosis regions.

use in endemic

One of major factor to develop MDR in bacteria is efflux of drugs by bacteria. There is no safer efflux pump inhibitor to be given as an adjuvant clinically so far. Based on our finding of microbial EPI and results, can be the potential candidate for treating MDR TD with conventional anti-TB drugs and other infections caused by MDR gram positive bacteria

There is no drug against nosocomial/ hospital infections caused by Gram negative bacteria once the fourth generation ~-lactam/carbapenem fails . There is a single antibiotic i.e. Colistin (Polymyxin E1/E2) is given. Few cases are already reported for its resistance. Our present progress expected to give polymyxin variant (A 1, A2) with better therapeutic efficacy and less toxicity

Patient friendly Anti-TB drug with new concept

TRL4

TRL4

TRL2

VIII. Novel non-lactam inhibitors Non-lactam J3-lactamase inhibitors TRL4 of 12>-lactamase for treatment are not reported so far and diagnosis of Mycobacterium tuberculosis

IX. Established the platforms for in vitro and in vivo A platforms for in vitro and in vivo testing of various testing of various TRL3 preparations ( extracts/fractions/compoun ds) for antimalarial activity.

X. Few leads, exhibiting in vitro preparations(extracts/fractions/comp TRL2 antimalarial activity ounds) for antimalarial activity (identified in collaboration

with Dr. R.S. Jolly), may have potential in antimalarial drug development

XI. Identified two leads that Identified two leads that have TRL2 have specific antitubercular specific antitubercular activity could activity, could kill Mtb cells kill Mtb cells at sub-micromolar at sub-micromolar cone. concentrations

XII. Yeast based High throughput screening New high throughput screening method setup for screening method against a-synuclein natural extracts against a- toxicity synuclein toxicity, one of the important target in neurodegenerative disorders

TRL2

2. Technology/Product developed: Number and names with TRL level of Development: Following at different TR levels

i. Immunosuppressant for use in organ transplant- TRL5

ii. Therapeutic and preventive treatment of secondary iron overload-TRL4

iii. Immunosuppressant for use in arthritis by generating Tregs -TRL4

iv. An immunosuppressant in delaying organ transplant-TRL4

v. Efflux pump inhibitor (EPI) isolated from microbial source as adjuvant to treat TB as well as other infections caused by Gram positive MDR bacteria- TRL4

vi . Polymyxin variant (A 1, A2) as solution to treat nosocomial and hospital infections by MDR Gram negative bacteria and its microbial process for production - TRL4

vii. Novel non-lactam inhibitors of 11-lactamase for treatment and diagnosis of Mycobacterium Tuberculosis -TRL4

3. Technology/Product transferred : Number and names with name of licensee(s) : NIL

4. Facility created : Number and names with uniqueness & utility:

Significant revenue is expected from following animal models developed in facility

a. Transgenic mice facility

b. Mouse model for allogenic skin graft

c. Mouse model for secondary iron overload

d. Mouse model for arthritis

e. Mouse model for Asthma

f. Mouse model for Infection, Inflammation, thrombosis, type II diabetes

5. Sponsored projects obtained (with details): NIL

6. External Cash Flow (ECF) generated: NIL

7. Societal impact created (quantified data):

• Immunosuppressant for use in organ transplant

• Relief to patients with secondary iron over load condition (for example !3-thalassemia)

• An immunosuppressant for use in arthritis

• Adjuvant for MDR, XDR TB treatment

• Better alternative for treatment of serious hospital infections

• A lead in specific antitubercular activity at sub-micromolar concentrations could be a future potential anti-Tb drug

• Novel non-lactam inhibitors of r..-lactamase for treatment and diagnosis of M Tuberculosis

• Yeast based screening method against a-synuclein toxicity will be helpful in modern drug discovery in controlling neurodegenerative disorders

• 30 PhDs produced in terms of societal impact as HR development -@Rs. 60.00 Lakh/PhD and 27 Project fellows trained in terms of societal impact -@Rs. 18.00 Lakh/Fellow makes significant difference in nation's intellect building.

ROI: 30 PhDs X @Rs. 60.00 lakhs = Rs. 1800 lakhs; 27 Project Fellows X @Rs. 18.00 lakh = Rs. 486 lakhs

Total: 2286 lakhs

@Based on the Kelkar Committee Recommendations 2004 and Accounting for inflation

b. Outputs:

1. Periodic Reports Submitted: Yes

2. Publications

i. Total number: 46 (more in pipeline)

ii. Cumulative IF (as per 2015 IF table): 203.23

iii. Average IF: 4.50

iv. Average IF/Scientist: 22.50

3. Patents (or other forms of IP generated such as Copyrights, Designs etc.)

i. Filed: 4

• Singla AK, Agrewala JN, Vohra RM, Jolly RS. Caerulomycin A, as an immunosuppressive agent. United States Patent No. 8, 114,895, China (CN101287465), PCT (W02007031832), on February 14, 2012. Also granted in South Africa (2608/2009), Japan (26/04/2013, Korea (20/05/2014), EPO, Germany, France, Great Britain (03/06/2015)

• Jolly RS, Sharma AN, Mishra P, Vaid B, Khatri N. Immunosuppressive agents, derivatives thereof, 0178NF2016.

• Raghava GPS, Gautam A, Nandanwar HS. Cell Penetrating Peptide for Biomolecule Delivery. 3380DEL2013

• Kartha KPR, Kuppala R, Govindrajan M, Bhutani KK, Nandanwar HS. Recenoleic acid glycoside compounds as antibacterial agents 1885DEL2015.

To be filed in next 2-3 months

• Jolly RS, Sharma AN, Mishra P, Vaid B, Khatri N. Agents for iron chelation therapy.

• Jolly RS, Sharma AN, Mishra P, Vaid, Khatri N. Cytotoxic agents comprising new 2,2'-bipyridines

ii. Granted: One

iii . Licensed: NIL

4. Human Resource generated

i. PhD fellows (give PhDs completed & pursuing separately)

PhD completed:14

PhD submitted:?

PhD pursuing:9

Total: 30 PhDs

ii. Project fellows: 27 Project Fellows

iii. Skills imparted (Including skill set developed for technical services/ consultancy/ training purposes)

- Training on various tools and techniques in modern drug discovery from microbial origin for different targets in human health hazards

- Screening of microbial extracts for anti-Candida activity using a high throughput screening system

- Use of HTS for screening chemical libraries and microbial/ other extracts.

- One Senior Project assistant trained in protein chemistry, and biochemical assays

- Culturing of P. falciparum culture, in vitro and in vivo testing (in mouse model) of anti-malarial compounds

- Animal and microbial cell culturing techniques; isolation and screening of microbial extracts for NFkB inhibition in T cell leukemia and anti microbial activity

- Yeast based High throughput screening method setup for screening natural extracts against a-synuclein toxicity

- Screening of inhibitor against bacterial biofilm

5. External collaborations established: NIPER, Mohali (Punjab)

s. Lead/Techno Salient TRL of IP Status Status of No. logy/Product Features of the the of DPR/Co

(listed above Lead/Technology/ Lead/ Lead/Tee mmercial in outcomes) Product Technol hnology/ Technica

ogy Product I /Product Reportof

Lead/ Technol ogy/ Product

1. lmmunosupressant: TRL-5 Patent DPR not Lead 1: Present molecule is applicatio prepared lmmunosuppr expected to be devoid n filed yet essant for use of some of the toxicity in organ issues of currently transplant used drugs in clinic.

Moreover, our molecule is expected to considerably lower the cost of therapy.

Lead 2: Relief from TRL-4 Patent DPR not Therapeutic secondary iron applicatio prepared and overload: huge n to be yet preventive societal and economic filed in treatment of value for the product is next 2 to secondary expected. Currently, 3 months iron overload- only one (or two) drugs TRL4 (2 leads have been approved in back-up) by FDA for the

purpose, leaving excellent potential for developing newer molecules

2. Lead 1: Immunosuppressant TRL-4 Patent Product: lmmunosuppr to treat arthritis and filed immunos essant for use delay of organ uppressa in organ transplants by nt; DPR transplant- generating regulatory not TRL4 T cells (Tregs). Tregs prepared

are considered crucial yet in the suppression of arthritis and prevention of organ rejection. Tregs generated by CaeA will be used to delay the rejection of organ transplants and treatment of arthritis.

Lead 2: Use of molecules of TRL-2 Patent Immune-TDB/NOD-2 innate immunity is filling modulate ligand: gaining momentum as under r for immunomodul a novel therapy to progress treating ation to modulate the immune TB; DPR decrease the system against the not dose and pathogens. prepared duration of TB lmmunomodulator yet drugs regime TDB is used with

adjunct therapy with TB drugs to decrease the dose and duration of TB drug regime.

3. Lead 1: One of major factor to So far Efflux pump develop MDR in there are inhibitor (EPI) bacteria is efflux of TRL-4 only two Demonstr isolated from drugs by bacteria. EPis are ated in microbial There is no safer efflux reported vitro; source as pump inhibitor to be from DPR not adjuvant to given as an adjuvant microbial prepared treat TB as clinically so far. Based source & yet well as other on our finding of these are infections microbial EPI and non-caused by results, can be the commerci Gram positive potential candidate al. MDR bacteria for treating MDR TD Producer

with conventional strains anti-TB drugs and are other infections different caused by MDR gram than positive bacteria reported.

Chemical nature is Strain to different be than improved/

Lead 2: There is no drug TRL-4 reported. designed Polymyxin against nosocomial/ Patent to for higher variant (A 1, hospital infections be filed . productivi A2) as caused by Gram ty. DPR solution to negative bacteria once There is not treat the fourth generation no prepared nosocomial 13-lactam/carbapenem commerci yet and hospital fails. There is a single al infections by antibiotic i.e. Colistin productio MDR Gram (Polymyxin E1/E2) is n for it. negative given. Few cases are At bacteria and already reported for its present, its microbial resistance. Our colistin process for present progress (E1 & E2) production expected to give is sold

polymyxin variant commerci (A 1, A2) with better ally as the theraputic efficacy best and less toxicity effective

variant. Our variant is having better activity and low cyto-toxicityPat ent not filed

4. Lead 1: The process of drug New drugs which will TRL-2 New proof DPR in design and be cleaner even if less of the testing potent and may be of concept process against few immense use in of select NRs. Tuberculosis endemic preparati Lead to new regions on drugs which will be cleaner (even if less potent), may be of immense use in Tuberculosis endemic regions.

5. Identified two Could kill Mtb cells at TRL-2 Patent not DPR not leads that sub-micromolar filed prepared have specific concentrations and yet antitubercular could act as lead activity. compounds.

6. Lead-1: Novel non-lactam Non- lactam P- TRL-4 Non- DPR not inhibitors of lactamase inhibitors lactam ~- prepared 1?>-lactamase are not reported so lactamase yet for treatment far inhibitors and diagnosis are not of reported . Mycobacteriu Patent m filing in tuberculosis the

process

7. Lead-1: Established A platforms for in TRL-3 Helpful in DPR not the platforms vitro and in vivo drug prepared for in vitro testing of various discovery yet and in vivo preparations for testing of (extracts/fractions/com antimalari various pounds) for als, preparations( antimalarial activity Patent not extracts/fracti filed ons/compoun ds) for TRL-2 antimalarial DPR not activity prepared

yet Lead-2: Few Potential leads, leads in exhibiting in antimalari vitro al drug antimalarial developm activity ent. (identified in Patent not collaboration filed with Dr. R.S. Jolly), may have potential in antimalarial drug development

8. Identified two leads that have specific Identified two leads TRL-2 Possible DPR to antitubercular that have specific anti-Tb be activity, could antitubercular activity drug. prepared kill Mtb cells could kill Mtb cells at Patent not at sub- sub-micromolar filed micromolar concentration concentration s

9. Yeast based High throughput New high throughput TRL-2 One of DPR not screening screening method the prepared method setup against a-synuclein important yet for screening toxicity target in natural neurodeg extracts enerative against a- disorders synuclein toxicity, one of the important target in neurodegener ative disorders

6. SectoraiMonitoring Committee Recommendations on Lead/Technology/Product (listed above):

Criteria SMC Recommendations Name of LeadfTechnology /Product 1. EPI as the drug potentiator in conventional TB treatment

2. HTS screen for drug against neurodegenerative disorders, against a-synuclein toxicity-followup of identified microbial extracts

3. Non-lactam beta-lactamase inhibitor Is the Lead/ Technology/Product Yes worth taking up further? What is the further R&D efforts that 1. Toxicity studies of identified EPis. Best to outsource it to need to be put by CSIR/CSIR organization such as NIPER, Mohali who have extensive laboratories? expertise in the field. This has to be followed by clinical

studies/trials 2. The established platform for HTS against neurodegenerative

diseases is already complemented with neuronal cells. Pure active compounds from extracts needs to be identified and leads need to be tested in animal models of neu rodegenerative diseases.

3. There is strong requirement of a medicinal chemist. A CRO will be hired for further lead-optimization and preclinical studies of beta-lactamase inhibitor.

Global benchmarking of the 1. No EPI is used clinically so far due to several issues of LeadfTechnology/Product drugability/or as adjuvant. Thus a less toxic and target oriented specifically wrt specifications and EPI would be identified. cost 2. Currently there is not cure for neurodegenerative diseases.

Thus attempts will be made to identify novel and effective therapeutic agents.

3. Alternative to commercially available beta lactamase inhibitors with higher efficacy and lower toxici!J'.

Is the LeadfTechnology/Product worthy of commissioning a DPR at this stage?

What are the likely resources and Financial support is needed for about 3-5 years. time duration required for taking forward the identified Lead/ Technology/Product to the desired TRL? Potential stake holders who may be Any Pharma major in India/Abroad with substantive expertise appropriate to partner technically as and financial resources to transform leads to drugs well as financially Suggestion for plausible road map 1. EPI: Derivatives of the chemical scaffolds will be synthesized towards further development of based on rationales and will be tested. In vivo studies will be lead/technology/product for conducted. achieving desired TRL 2. Anti neurodegeneratives : active compound identification from

already selected extracts, and further testing in Animal models.

3. Non-lactam beta lactamase: lead compound optimization and preclinical studies

GO/NO GO further development Go Other suggestions, if any, related to benefits/usage/ commercialization

7. Identified "lessons to be learnt", especially from shortcomings/failures.

NA

8. Comments on financial progress on the project - fund availability and utilization of fund in the project:

The financial progress is satisfactory and the investment made is justified.

9. Sectoral Monitoring Committee Recommendations on Facility creation or other outcomes:

10. Grading of Project Execution: Outstanding /Excellent N.Good/Good/ Satisfactory/ Un-satisfactory

Good.

11. Additional comments, if any:

Signature of Chairman & all Members of Sectoral Monitoring Committee

~ Dr.C.M.~

(Member)

~ Dr. T.S. Balganesh

(Member)

~ys£~vc~ o .. ~·· ' Dr~~~ber) (Member)

{.\JJ Prof P. Kondaiah

(Member)

Dr. M.K. Gurjar (Member)

/J!rrl~Jh Dr. S. Srikanth (Member)

~~;r Director, CSIR-IICB (TF Chairman-Member)

Director, CSIR-IMTECH (TF Chairman-Member)

cL~ Director ~iR-IGIB

(TF Chairman- Member)

Director, CSIR-IICT (TF Chairman • Member)

Director, CSIR· NEIST (TF Chairman -Member)

~' Prof. M.K. Bhan (Chairman)

M.~~ Director, CSIR-CDRI

(TF Chairman -Member)

R~~ Director, CSIR-IIIM

(TF- Chairman-Member)

Director, CSIR-NCL (TF Chairman • Member)