Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5

June/July 2020 Report
Regeneron - https://www.regeneron.com- Regeneron is a leading biotechnology company that was founded over 30 years ago
o Company is led by physician-scientistso Developed 7 FDA-approved treatmentso Have 20+ product candidates in clinical development across multiple
therapeutic areaso Published over 200 peer-reviewed publications in 2019
o 8100+ employees worldwide- Their medicine and pipeline are designed to help patients with eye disease, allergic
and inflammatory disease, cancer, cardiovascular and metabolic diseases, infectious
diseases, pain and rare diseases- All drug candidates are invented and developed in-house- Regeneron focuses on therapeutic antibodies
o They engineer therapeutic antibodies that specifically recognize drug targets- The company does not limit its innovations to any one therapeutic areao They are open to collaboration opportunities with the potential to offer
important benefits to patients- Leadershipo The company has multiple Nobel Naureates and 5 members of the National
Academy of Science among its leadershipo Was one of the first companies to form a Science and Technology Committee
as part of its Board▪ This has now become industry standard- Current collaborators:o Bayero Sanofio Icahn School of Medicine at Mount Sinaio Colunbia Universityo Teva Pharmaceuticals
o Intellia Therapeutics
o Adicet Bioo Alnylam Pharmaceuticals- 2019 Financial report: https://investor.regeneron.com/static-files/cbebda5b-c02d466b-8be9-e0d8a4052cf8- Pipeline drug candidates currently undergoing clinical testing:- https://investor.regeneron.com/static-files/cbebda5b-c02d-466b-8be9e0d8a4052cf8- Proprietary technologies include: VelociSuite®

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5o VelociGene® enables rapid, automated and high-scale manipulation ofmouse DNA with almost no limitations on the size and sophistication ofmodifications▪ Enables unprecedented speed and capacity for the validation oftherapeutic targets and the creation of animal models of humandisease▪ Target validation▪ Traditional technologies for producing genetically modified mice wereslow and labor-intensive▪ This led to the development of VelociGene▪ A core element of VelociGene technology are Bacterial Artificial
Chromosomes (BAC) which are used to manipulate the mouse DNA▪ The unique properties of BACS allow the deletion or insertion of verylarge pieces of DNA → resulting in BACVec: these permit the complete
humanization of the variable regions of antibody genes that empower
the use of the drug discovery platform VelocImmune▪ The engineered BACVec is delivered into mouse embryonic stem cells
which are progenitor cells that ultimately produce every other cell inthe mouse▪ Once introduced into the ES cells, the BACVec replaces the target genewith unmatched precision through a process called Homologous
Recombination▪ A key component of VelociGene is the Loss of Allele Assay which usedthoroughly automated and scalable processes to rapidly identify
embryonic stem cells with the desired genetic modification among thevast majority of non-targeted cells▪ VelociGene offers the fastest path to modifying very large portions of
the mouse genome with unmatched precision▪ VelociGene is a critical step in the drug discovery process at
Regeneron such as the creation of VelocImmune mice which are used
to produce fully human antibodies
o VelociMouse® - enables the immediate generation of genetically alteredmice directly from modified embryonic stem cells▪ The modified stem cells are injected in to the mouse embryo at a very
early stage to ensure that the resulting mice are completely derived ofthe modified embryonic stem cells▪ After the genetic modified embryo is implanted into a surrogate
mother, the first generation of mice born now directly contain thedesired genetic modifications• Avoid the need to breed multiple generations▪ This dramatically shortens the time needed to engineer geneticallymodified mice while reducing costs and improving precision

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5

Together, VelociGene and VelociMouse offer the fastest path tovalidate the function of possible targets for drug discovery▪ Using these technologies to produce preclinical disease models inorder to study a disease in more detail or to determine the efficacy ofa new drug allows for Regeneron to have higher confidence in a
potential therapeutic solution for humans at an earlier stage in theprocesso VelocImmune® - Regeneron’s unique technology for producing fully humanmonoclonal antibodies▪ Creates a multitude of optimized antibody drug candidates efficiently
and directly from immunized mice
▪ By injecting the previously identified drug protein into the mice, aninfection is simulated and the immune system is triggered to produce
a multitude of target specific antibodies▪ Conventional methods require the subsequent humanization of these
antibodies to reduce rejection by the patients’ immune system▪ VelocImmune overcomes the limitations of traditional platforms by
rapidly creating fully human antibodies that tightly bind totherapeutic targets and avoid potential immune responses that may
occur in patients receiving antibodies that contain nonhuman
components▪ In VelocImmune mice, the gene’s coding for the variable regions ofantibodies are precisely replaced by their human counterparts using
VelociGene and VelociMouse technologies▪ By keeping the constant region of the antibody gene of mouse origin
to avoid compromising the immune system, VelocImmune triggers astrong immune response and takes advantage of the natural processthat produces a broad diversity of high quality antibodies▪ VelocImmune mouse if one of the largest genetic engineering projects
every undertaken in mammals▪ theseo VeloviMab® - a group of technologies that allow Regeneron to move with
unprecedented speed from identification of a therapeutic antibody into
clinical studies▪ VelociMab technologies used Flow cytometry of FACS
▪ Enables the high-throughput screening of potential therapeutic
antibodies and the rapid generation of cell lines for recombinanthuman antibodies• With the high through-put automated method, cells arelabelled with a fluorescent dye and sorted at up to 70 thousandcells per second according to specific characteristics▪

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5

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From these, VelociMab is able to quickly identify and isolated
the thousands of cells producing the antibody with thetherapeutically desirable properties• The genetic blueprint for each of these antibodies are thentransferred from mice into cells using ESSYR technology
developed at Regeneron• Antibody producing cells are identified by FASTR and NICE
technologies• In this step, the mouse constant region is replaced by humanconstant region• The cells can then produce antibodies in sufficient quantities toallow pre-clinical testing for the antibody with the best safety
and efficacy characteristics▪ Once the most promising target-specific antibody producing cell isselected, a seamless jump to clinical testing is possible because thecell liens used for testing are already capable of producing thousandsof litres of antibodies in specialized bioreactors▪ With the combination of VelocImmune and VelociMab, Regeneron has
shortened he timeline and increased the efficiency of fully humanantibody development for clinical use▪ Allows researchers to go from mouse immunization to production cellline bioreactor harvest within 8 months
VelociT™ - their unique mouse technology for producing fully humantherapeutic T-cell receptors (TCR) against tumor and viral antigens▪ Used as part pf Regeneron’s efforts to discover and develop novel
immune-oncology therapeutic candidates and assist collaborators in
producing fully human therapeutics TCRs
VelociHum™ - Regeneron’s immunodeficient mouse platform that can beused to accurately test human therapeutics against human immune cells andstudy human tumour models▪ VelociHum mice have been optimized to allow for better developmentof human immune cells in vivo through genetic humanizations▪ This also allows for engraftment of primary patient-derived tumoursthat do not take in other commercially available mice
Veloci-Bi® - allows for the generation of full-length bispecific antibodies
similar to native antibodies that are amenable to production by standard
antibody manufacturing techniques, and likely to have favorable antibodylike pharmaco kinetic properties
Regeneron Trap technology - creates circulating “decoy receptors” capableof reducing or eliminating the harmful effects of a signaling protein
EESYR – provides site-specific integration into a transcriptional hot spot in
the eukaryotic cell genome

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5

Results in rapid isolation of cells capable of high-level expression ofrecombinant therapeutic proteinso FASTR – a quantitative cell surface display technology that enables the use offlow cytometry to select eukaryotic cells that secrete the highest levels ofrecombinant therapeutic proteinso NICE – enables the control of the expression of secreted, recombinant
therapeutic proteins in eukaryotic cells▪

Regeneron Genetics Center®
- Regeneron Genetics Center® is a uniquely integrated research initiative that seeks
to improve patient care by using genomic approaches to speed drug discovery anddevelopmento One of the words largest human genomic research efforts
o They collaborate with a large network of collaborator institutions to gather
and analyze data, exchange expert perspectives, and search for discoverieso Some collaborators:▪ Geisinger Health System▪ UK Biobank▪ Accelerated Cures Project▪ Columbia University Medical Center▪ The Florey Institute of Neuroscience and Mental Health on Behalf of
the Australia and New Zealand MS Genetic Consortium- Scientists from the Regeneron Genetic Center were the first to identify a variant in
the HSD17B13 gene that is associated with reduced risk of, or protection from,various chronic liver diseases for which there are currently no approachedtherapeutics- They are now collaborating with Alnylam to discover potential RNAi therapies forthis target- Regeneron Genetics Center® is collaborating with the Hospital for Sick Children(SickKids) to study the genetic determinants of infantile and pediatric onset cases of
IBD through exome sequencing and analysis of families- On February 28, 2020, the Regeneron Genetics Center® celebrated the sequencing
of its 1,000,000th exome
FDA-approved Medicines- Arcalyst (rilonacept) injection for Subcutaneous Use – used to treat CryopyrinAssociated Syndromes including Familial Cold Autoinflammatory Syndrome (FCAS)
and Muckle-Wells Syndrome (MWS)- Dupixent (dupilumab) injection – used to treat atopic dermatitis and an add-on
maintenance treatment for moderate-to-severe asthma and chronic rhinosinusitis
with nasal polyposis

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5---

Eylea (aflibercept) Injection – used to treat Neovascular Age-related Macular
Degeneration, Macular Edema following Retinal Vein Occlusion (RVO_, Diabetic
Macular Edema (DME), and Diabetic Retinopathy (DR)Kevzara (sarilumbab) injection – used to treat moderately to severely active
rheumatoid arthritis
Libtayo (cemiplimab-rwlc) injection – used to treat patients with metastatic
cutaneous squamous cell carcinoma or locally advanced CSCC who are notcandidates for curative surgery or curative radiation
Praluent (alirocumab) injection - to reduce the risk of myocardial infarction,
stroke, and unstable angina requiring hospitalization in adults with establishedcardiovascular diseaseo As an adjunct to diet, alone or in combination with other lipid-lowering
therapies (e.g., statins, ezetimibe), for the treatment of adults with primary
hyperlipidemia (including heterozygous familial hypercholesterolemia) to
reduce low-density lipoprotein cholesterol (LDL-C).

News
BARDA Procures Regeneron’s REGN-EB3 Investigational Ebola Treatment for National
Reparedness- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced on July 19th thatthe Biomedical Advanced Research and Development Authority (BARDA), part of
the Office of the Assistant Secretary for Preparedness and Response within the U.S.
Department of Health and Human Services (HHS), has entered into an agreement toprocure REGN-EB3 as part of the HHS' goal of building national preparedness for
public health emergencies.
- REGN-EB3 is Regeneron's investigational triple antibody cocktail treatment for
Ebola virus infection and is currently under Priority Review by the U.S. Food andDrug Administration (FDA), with a target action date of October 25, 2020.
- Contingent on FDA approval, Regeneron expects to deliver an established number oftreatment doses over the course of six years and receive compensation of
approximately $10 million in 2021 and an average of $67 million per year for eachof the next five years (2022-2026).
Regeneron Announces Manufacturing And Supply Agreement For Barda And U.S.
Department Of Defense For Regn-Cov2 Anti-Viral Antibody Cocktail- Regeneron Pharmaceuticals, Inc. announced on July 7 th that the Biomedical
Advanced Research and Development Authority (BARDA), part of the Office of theAssistant Secretary for Preparedness and Response at the U.S. Department of Healthand Human Services, and the Department of Defense Joint Program Executive Officefor Chemical, Biological, Radiological and Nuclear Defense have awarded Regenerona $450 million contract to manufacture and supply REGN-COV2.

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5-

REGN-COV2 is Regeneron's investigational double antibody cocktail that is currently
in two Phase 2/3 clinical trials for the treatment of COVID-19 and in a Phase 3
trial for the prevention of COVID-19 infection.

Regeneron And Sanofi Provide Update On Kevzara® (Sarilumab) Phase 3 U.S.
Trial In Covid-19 Patients- Regeneron Pharmaceuticals, Inc. and Sanofi announced on July 2, 2020 that
the U.S. Phase 3 trial of - - Kevzara® (sarilumab) 400 mg in COVID-19 patientsrequiring mechanical ventilation did not meet its primary and key secondary
endpoints when Kevzara was added to best supportive care compared to best
supportive care alone (placebo).
- Minor positive trends were observed in the primary pre-specified analysis group(critical patients on Kevzara 400 mg who were mechanically ventilated at baseline)that did not reach statistical significance, and these were countered by negative
trends in a subgroup of critical patients who were not mechanically ventilated atbaseline.
- Serious adverse events that occurred in at least 3% of patients and more frequently
among Kevzara patients were multi-organ dysfunction syndrome (6% Kevzara, 5%
placebo) and hypotension (4% Kevzara, 3% placebo).
- Based on the results, the U.S.-based trial has been stopped, including in a second
cohort of patients who received a higher dose of Kevzara (800 mg).
- A separate Sanofi-led trial outside of the U.S. in hospitalized patients with severe
and critical COVID-19 using a different dosing regimen is ongoing.
Fda Approves New Dupixent® (Dupilumab) Pre -Filled Pen Designed To
Support More Convenient Self-Administration- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that
the U.S. Food and Drug Administration (FDA) has approved a 300 mg single-dose
pre-filled pen for Dupixent® (dupilumab).
- The pre-filled pen is approved for all Dupixent indications in patients aged 12 years
and older, which includes use in certain patients with atopic dermatitis, asthma andchronic rhinosinusitis with nasal polyposis (CRSwNP), for at-home administration.
- This new pre-filled pen will provide patients with a more convenient option foradministering Dupixent.
- The 300 mg pre-filled pen is expected to be available in the U.S. in the third quarterof 2020.
- The pre-filled pen features a hidden needle and single-press auto-injection, alongwith visual and audio feedback to help with administration.
- Regeneron and Sanofi are working with the FDA to provide additional data theyrequire to complete their review of the 200 mg pre-filled pen

Eugene Consulting Inc.
1602- 111 St. Clair Ave W
Toronto, ON
M4V 1N5--

Dupixent is a fully-human monoclonal antibody that inhibits the signaling of theinterleukin-4 (IL-4) and interleukin-13 (IL-13) proteins, and is not an
immunosuppressant.
Data from Dupixent clinical trials have shown that IL-4 and IL-13 are key drivers of
the type 2 inflammation that plays a major role in atopic dermatitis, asthma and
CRSwNP.