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3.2. DRUGS INDICATED FOR ONCOLOGICAL DISEASES A large number of the pipeline drugs are indicated for oncological diseases. Companies such as Amgen, Merrimack and Genentech are developing these anti-cancer bispecific antibodies. It is common to see that a drug is simultaneously being tested for several indications. For example, catumaxomab, which has approval for malignant ascites, is being tested for its role in ovarian and gastric cancer in phase II clinical trials. Drugs such as blinatumomab and duligotumab are also a part of one drug - several applications list. Table 3.1 tabulates the oncological bispecific antibody drugs and provides information such as target antigen, indication and the phase of development.

Table 3.1 Oncological Bispecific Antibodies in Clinical Trials

S. No. Drug Target Antigen Collaborators Technology Indication Phase of Development INDUSTRY DRUGS 1. Blinatumomab / CD3 x CD19 Amgen BiTE ALL, DLBCL, 2, 2, 2 MT103 / MEDI- NHL 538

2. CD20Bi / FBT- CD3 x CD20 Fresenius Biotech, Triomab B Cell 1 / 2 A05/ Lymphomun Trion Pharma Malignancies SAMPLE PAGES

Report Page 33 3. TF2 CEA x HSG Immunomedics Dock and Lock Pretargeting and 1 / 2 Imaging - Cancer

4. Catumaxomab EpCAM x CD3 Fresenius Triomab Malignant Ascites, Marketed, 2, 2 (Removab) Biotech GmbH, Gastric cancer, Trion Ovarian cancer

5. MM-111 HER2 x HER3 Merrimack HSA-body Gastric cancer; 2, 1, 1 Pharmaceuticals Advanced, Refractory Her2 Amplified, Heregulin Positive Cancers; HER2 positive solid tumours 6. Duligotumab EGFR x HER3 Genentech Two-in-One Metastatic 2, 2 Dual Action colorectal cancer, Fab (DAF) Recurrent / metastatic SCCHN

7. Solitomab EpCAM x CD3 Amgen BiTE Solid Tumors 1 (AMG110, MT110)

Continued on Page 34, 35, 36, 37, 38

DULIGOTUMAB / MEHD7945A / RG7597 (ROCHE / GENENTECH)

4.4.1. OVERVIEW Duligotumab is a bispecific antibody drug in development by Roche. It is based on the Genentech’s two-in-one technology. The technology was developed by scientists working at the Antibody Engineering and Protein Engineering Department at Genentech. The basis of ‘two-in-one’ technology is the introduction of certain mutations in the Fv region, such that each Fv region in the antibody has affinity for two different antigens. However, at any given time each Fv region will bind to any one of the two recognised antigens; this is essentially because the two antigens are recognised by a similar set of antigen binding residues.

The drug is currently being tested in phase II clinical trials for its role in treatment of recurrent / metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS positive relapsed / refractory metastatic colorectal cancer (mCRC). The drug is also in phase I for the indication of metastatic epithetlial tissues. It first entered clinical development in 2010.

4.4.4. COMPETITION FOR DULIGOTUMAB Table 4.6 highlights the competitive drugs for duligotumab. Erbitux and Vectibix are antibody basedSAMPLE therapeutics approved for the treatment of KRAS PAGES wild type mCRC, the same indication as duligotumab. Erbitux is the closest competitor and the active comparatorReport in clinical Page trials 55 for duligotumab.

Annual treatment cost for treatment of colorectal cancer with Erbitux is around USD 140,000 per patient. Duligotumab is likely to have an advantage over Erbitux with respect to the dosing schedule. Unlike Erbitux, which is administered through intravenous infusion every week, duligotumab is being tested for intravenous administration every two weeks.

Table 4.6 Duligotumab / MEHD7945A / RG7597: Competitor Drug Analysis

Drug Company Indication Type of Drug Route of Administration Erbitux BMS, Eli Lilly KRAS wild type Recombinant Intravenous infusion (Cetuximab) mCRC, SCCHN human/mouse chimeric mAb Vectibix Amgen KRAS wild type mAb Intravenous infusion (Panitumumab) mCRC Xeloda (Capecitabine) Genentech mCRC Small molecule Oral Stivarga (Regorafenib) Bayer mCRC Small molecule Oral Zaltrap Regeneron / Sanofi mCRC Recombinant fusion Intravenous infusion (ziv-aflibercept) protein

Source: Roots Analysis

4.9.2.1. MM-111: CURRENT DEVELOPMENT STATUS The drug is in trials for several indications such as gastric cancer and breast cancer. MM-111 is in phase II trials as a combination therapy with paclitaxel, or paclitaxel and trastuzumab in patients with advanced gastric, esophageal and gastroesophageal junction cancers. The company started patient enrollment on this trial in July 2013 and expects to enroll 180 patients across centers in the US, Europe, Asia and Africa. The drug is also in phase I trial for treatment of refractory Her2 amplified, heregulin positive breast cancer.

Merrimack Pharmaceuticals is also developing a companion diagnostic tool that will help identify patients likely to respond to treatment with MM-111 based on their expression levels of ErbB2 (HER2), ErbB3, heregulin and other factors that the trials will suggest. Table 4.14 describes the ongoing trials for the drug.

4.9.4. MM-111 SALES FORECAST: LONG TERM, 2018 - 2023 Figure 4.15 and Table 10.33 highlight the ‘base scenario’ sales forecast of MM 111. The sales forecasts are based on the expectation that the drug will receive market approval in 2018. SAMPLE PAGES Figure 4.15 MM-111 Market (USD MM), Long Term Forecast:Report 2018 Page - 2023 (Base74 Scenario)

20 12 8

2018E 2019E 2020E 2021E 2022E 2023E

Source: Roots Analysis

Under the ‘base scenario’, we forecast the drug to achieve sales of USD 8 million during its launch year. This is likely to grow rapidly to reach USD 79 million by 2023, representing a CAGR of 60%. The details of the conservative and the aggressive scenarios are listed in Tables 10.34 and 10.35 in the Appendices.

5.2. BISPECIFIC ANTIBODY PRODUCTION: TECHNOLOGY PROVIDERS AND AVAILABLE TECHNOLOGIES

The bsAbs market is flooded with companies that provide various bispecific creation technology platforms. These offer technologies belonging to the first and the latest generations of bispecific antibodies. Table 5.2 tabulates these technology providers along with their bispecific antibody technology platforms.

Table 5.2 Bispecific Antibody Technologies Platforms

S. No. Company Technology

First Generation

1. Trion Pharma Triomab Second Generation

2. AbbVie DVD-Ig

3. Ambrx Not declared

4. Adimab Adimab technology

5. Ablynx Nanobodies

6. Allozyne CAESAR Biociphering Electrostatistically Matched SAMPLEAmgen PAGES 7. F(ab)2 (Micromet) Report Page 90 BiTE

8. AstraZeneca (MedImmune) Tx2Ab

9. Baliopharm Chemical Crosslinking Beijing ABT Genetic Engineering 10. scBsAb Technology Co.

11. Biogen-Idec Hercules

12. Biotecnol Tribody Technology

13. Bicycle Therapeutics Bicycle technology

14. Covagen FynomAb

15. Dutalys DutaMab

16. Epigen Biotech COMBODY

17. EMD Serono Seed (Strand-Exchange Engineered Domain) Body 2 18. F-star (mAb ) Luz-Y (Use of Leucine Zippers)

Two In One 19. Genentech Knob-into-Holes

Bis-Fab/ DAF (Dual Action Fab)

Continued on Page 91, 92

5.3.3. BISPECIFIC T CELL ENGAGER / BiTE (AMGEN) BiTE technology was developed by Micromet based on research conducted at the University of Munich. A group of scientists from the University established Micromet in 1993, with headquarters in the US and a research facility in Germany. In March 2012, Amgen acquired Micromet for a payment of USD 1.16 billion. With this acquisition, Amgen gained the rights to BiTE technology platform and two pipeline molecules – MT103 in phase III and a yet unnamed molecule in phase I.

5.3.3.1. THE TECHNOLOGY BiTe based bispecific antibodies are formed by fusion of two scFv that have differing amino acid sequences or amino acid sequences from four different genes. Each BiTE bispecific antibody comprises of two scFv’s forming a single polypeptide of 55 kDa molecular size. Each BiTE antibody has a single N and C terminus. All BiTE antibodies recognise CD3 and another target antigen, which varies for each molecule.

5.3.3.2. DRUGS BASED ON BiTE Amgen, post acquisition of Micromet, has continued development of blinatumomab. Alongside, it also has developed other BiTE based bispecific antibodies. Furthermore, there are several more BiTESAMPLE antibodies in development by pharmaceutical companiesPAGES including Boehringer Ingelheim, Bayer, and MedImmune. Table 5.5 tabulates the drugs based on thisReport technology. PageThe BiTE 102 antibody farthest in clinical development is Blinatumomab, which is being developed in house by Amgen. The antibody is in phase II clinical trials for the treatment of NHL, ALL and DLBCL.

Table 5.5 Drugs based on BiTE Technology

Bispecific Target Cell Indicated Disease Phase of Collaborator / mAb Receptors Development Licensor Blinatumomab, CD19 X CD3 ALL, DLBCL, NHL 2, 2, 2 In-house MT103 Solitomab, AMG 110 EpCAM x CD3 Solid tumors 1 In-house MT111, MEDI 565 CEA x CD3 Gastrointestinal aden 1 MedImmune ocarcinomas (recruitment suspended) AMG 212, PSMA x CD3 Prostate cancer 1 Bayer BAY2010112 AMG 330 CD33 x CD3 AML Preclinical In-house Unnamed NA Multiple myeloma NA Boehringer Ingelheim Unnamed NA Solid tumour NA Bayer

NHL - Non Hodgkins Lymphoma, ALL - Acute lymphoblastic Leukaemia DLBCL - Diffuse Large B-cell Lymphoma, AML - Acute Myeloid Leukaemia

Source: Roots Analysis