Roots Analysis Pvt. Ltd.

Roots Analysis Pvt. Ltd.

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4.3 .

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The ADC development pipeline is rich and dynamic. There are several molecules in the clinical and preclinical stage. As of January 2014, there are around 40 molecules in various phases of clinical development (I-III) and the pipeline is continuously expanding. Majority of the drugs are being developed for oncological indications including non-small-cell lung carcinoma (NSCLC), breast cancer, solid tumours etc.

Tables 4.1 - 4.17 enlist the ADCs in various stages of clinical development, mentioning the cytotoxic drug and conjugated antibody in each.

Table 4.1 ADC Molecules in Clinical Development – Roche / Genentech

Drug Company Technology

Provider Indication Phase of Development Kadcyla/ Trastuzumab-DM1 (mAb anti-HER2 linked to toxin DM1)

Roche/Genentech ImmunoGen Metastatic Breast Cancer Approved Pinatuzumab vedotin/RG7593 (mAb anti-CD22 linked to toxin auristatin E)

Roche/Genentech Seattle Genetics Haematological Malignancies

II

RG7450 (mAb anti-STEAP1 linked to toxin auristatin E)

Roche/Genentech Seattle Genetics Prostate Cancer I

RG7458 (mAb anti-MUC16 linked to toxin auristatin E)

Roche/Genentech Seattle Genetics Ovarian Cancer I

RG7596 (mAb anti-CD79b linked to toxin auristatin E)

Roche/Genentech Seattle Genetics Hematological Malignancies

II

RG7598 (auristatin) Roche/Genentech Seattle Genetics Multiple Myeloma I RG7599 (mAb

anti-NaPi2b linked to toxin auristatin)

Roche/Genentech Seattle Genetics NSCLC, Ovarian Cancer

I

RG7600 (auristatin) Roche/Genentech Seattle Genetics Pancreatic, Ovarian Cancer

I

RG7636 (mAb anti-ETBR linked to toxin auristatin)

Roche/Genentech Seattle Genetics Melanoma I

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4.4.2.

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Table 10.2 and Figure 4.2 show the relative proportion of the number of marketed and clinical stage molecules by type of toxin.

Figure 4.2 ADCs in Clinical Development: Share (%) by Cytotoxin Used

Source: Roots Analysis

Auristatins are the most popular cytotoxins associated with ADCs. These synthetic antineoplastic agents are being extensively used by Seattle Genetics. Monomethyl auristatins (MMA) work by inhibition of cell division by blocking the polymerisation of tubulin. As they are highly toxic, their direct use can cause uncontrolled and unwanted cell death. MMA are used in two derivative forms, the uncharged MMAE and MMAF in which charged C-terminal phenylalanine residue attenuates its cytotoxic activity.

Other toxins such as maytansinoid are alsocytotoxic agents that inhibit assembly ofmicrotubules. Maytansinoids are synthetic derivatives of maytansine, which can be isolated from plants of the genusMaytenus. The use of this toxin in ADC is being deployed by ImmunoGen and other

licensees.

Duocarmycin is an alternative payload under development in ADC molecules. Duocarmycins are DNA alkylating agents being explored by Bristol-Myers Squibb (BMS) / Medarex and Synthon. BMS has an ADC (MDX-1203 – phase 1 clinical trials) comprising duocarmycin analogue linked to an antibody via a dipeptide linker. At the same time, Synthon currently has tested some ADCs using duocarmycin in preclinical studies, showing efficacy in low dose and safety in higher doses as

20, 48.8% 11, 26.8% 2, 4.9% 1, 2.4% 2, 4.9% 5, 12.2% Auristatin Maytansine Calicheamicin PBD Topoisomerase SN 38 Others

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Figure 5.1 depicts our analysis of the in-house or contract manufacturing of various steps of ADC manufacturing for 12 marketed and clinical stage molecules. Wherever information wasn’t readily available for confidentiality reasons, we have indicated our best guess based upon the research output. Furthermore, our interviews with several industry experts suggest that majority (70% – 80%) of ADC manufacturing is indeed outsourced.

Figure 5.1 ADCs: Matrix View of Outsourced Activities by Company

Legend

 Outsourced Activity  In-house Activity ? Information not available

Note: The Orange background indicates those cases where our research didn’t confirm the status of respective activities (due to the confidential nature of the businesses); mapping in these cases represents the ‘likely’ status based upon the partial information we were able to gather

Source: Roots Analysis

Specifically, for Adcetris, our research confirms that Seattle Genetics / Millennium outsource the various steps of ADC production to following CMOs:

S.No. Drug Company Antibody Linker Cytotoxin Conjugation Fill/Finish

1 Adcetris Seattle Genetics / Millennium (Takeda)      2 Kadcyla Genentech      3 CMC 544 Pfizer/Wyeth  ?    4 CDX-011 Celldex Therapeutics      5 SAR 3419 Sanofi Aventis ? ? ?  ? 6 BT-062 Biotest      7 PSMA ADC Progenics

Pharmaceuticals      8 RG7593 Roche      9 RG7596 Roche      10 IMMU-130 Immunomedics  ?    11 IMMU-132 Immunomedics  ?    12 ABT-414 AbbVie     

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As indicated in Figure 5.1, majority of the companies, including the leading technology providers – Seattle Genetics and ImmunoGen – are dependent on contract manufacturers to supply the components. The presence of contract manufacturers is justified by the complexity of ADC manufacturing, which requires clean room facilities for working with antibodies and high containment facilities for small molecule cytotoxic drugs.

Table 5.1 lists some of the contract manufacturers for ADC components. We have discussed, in detail, the capabilities of these and other CMOs in subsequent sections of this report.

Table 5.1 List of Contract Manufacturers and Their Capabilities in ADC

Manufacturing

Contract Manufacturers Antibody Production

HPAPI1/ Cytotoxic drugs

Linkers Conjugation Fill/Finish

Società Italiana Corticosteroidi S.r.l

Albany Molecular Research, Inc.

(AMRI) AbbVie (Abbott Contract

Manufacturing) Boehringer Ingelheim

Cytovance Biologics LLC

Sigma Aldrich Fine Chemicals

(SAFC) Baxter BioPharma Solutions

Lonza

Pierre Fabre Medicament

Production Piramal Healthcare Pharma

Solutions BSP Pharmaceuticals

Novasep

Carbogen Amcis

Fujifilm Diosynth Biotechnologies

Cambrex Corporation

Goodwin Biotechnology

Continued on the next Page

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There are limited number of contract manufacturers with capabilities for lyophilisation and fill/finish of cytotoxic drugs. These processes are required to be carried out within isolators for cytotoxic drugs such as ADCs. In 2011, one of the prominent contract manufacturers for cytotoxic injectable drugs, Ben Venue Laboratories, announced its plan to exit from the contract manufacturing business. The company was one of the few CMOs in the US with fill/finish capacity for cytotoxic drugs. Ben Venue Laboratories did the lyophilisation and filling for Pfizer’s ADC Mylotarg, which was later withdrawn from the US market.2 The company planned to exit from its contract manufacturing business due to the huge investment that was required for conforming its manufacturing facility to the FDA standards. The exit of Ben Venue has created opportunity for other CMOs in the market. However, our research reveals that there are still only very few CMOs in the US with capabilities for fill/finish of cytotoxic drugs.

Figure 6.4 highlights the location of fill / finish facilities of various CMOs.

Figure 6.4 ADC Fill / Finish: Worldwide CMO Facilities

Source: Roots Analysis

Similar analysis available for HPAPI and Conjugation facilities on Pages 56-62

2