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INO: Great Things Take Time, And Now’s the Time

11/04/2019

NASDAQ:INO

Addressing cancer with immuno-oncology (IO) has become one of the most exciting areas in biotechnology over the last decade. With the first approval of checkpoint inhibitors beginning in 2011 and CAR-T in 2017 a wave of new approaches has surfaced to address the second most common cause of mortality. With the advance of science, increased understanding of tumor markers and approval of other IO therapies, regulatory agencies have become more comfortable with the IO approach and are familiar with the pathway to approval. Along with efforts such as the 21st Century Cures Act and the Cancer Moonshot in 2016 which provided increased awareness and funding for the disease, advancements in the space have accelerated. Progress has clarified the value of combination and targeted therapies to enhance the ability of medicine to improve overall survival and cure.

One innovative competitor in the industry has been able to combine its well-validated immunotherapy technology with other cancer therapies to achieve meaningful successes in the fight against cancer. This company, called Inovio Pharmaceuticals Inc. (NASDAQ:INO), is developing a Phase III asset designated VGX-3100 which is expected to provide a top-line efficacy readout in 2020 followed by a final readout in 2021. The initial indication for VGX-3100 is high grade cervical dysplasia which is being investigated in two parallel Phase III programs called REVEAL 1 and REVEAL 2. Inovio has two other IO candidates for rare diseases that could enter the market prior to VGX-3100 and further validate the company’s approach to IO. These indications in recurrent respiratory papillomatosis (RRP) and glioblastoma multiforme (GBM) may qualify for expedited treatment and other special considerations providing significant value to stakeholders. The thread that ties together all of Inovio’s oncology pursuits is the underlying connection with various strains of human papilloma virus.

Human Papillomavirus

Human Papillomavirus or HPV is the number one sexually transmitted disease, most commonly spread by sexual contact. In most cases it resolves spontaneously; however, when it fails to retreat, the virus can cause warts and multiple types of dysplasias and cancer. The precancerous or cancerous lesions may appear in the male and female genitalia and in the mouth or throat. The virus belongs to the papovaviridae family and is an icosahedral capsid virus without an envelope, which enhances its survival in the environment. There are over 100 different strains of HPV, some of which can be addressed with vaccines such as Gardasil and Cervarix. However, the vaccine approach has limitations. Vaccines must be administered prior to exposure, vaccination rates are relatively low and the inoculation must be specific to the type of HPV encountered. Even though most persons’ immune systems clear HPV, many individuals do contract the infection and it may cause serious health problems. Dysplasias, precancers and cancer can surface many years after the initial infection. Of the numerous types of HPV, HPV16 and HPV18 are most commonly associated with genital and oropharyngeal dysplasias and cancers such as cervical dysplasia and head & neck cancer.

Exhibit I – Range of Abnormal Cells in the Cervix1

Cervical dysplasia, also known as cervical intraepithelial neoplasia (CIN), is characterized by abnormal or precancerous growth of cells in and around a woman’s cervix. It is typically asymptomatic and is detected through routine PAP smears, cancer screenings, colposcopy and pelvic examinations. If the disorder is suspected, a biopsy of the tissue may be taken to the laboratory to confirm diagnosis.

Exhibit II – HPV Infection and U.S. Market Incidence2

According to the World Health Organization (WHO), the HPV16 and HPV18 strains cause 70% of cervical cancers and dysplasias and are strongly implicated in anal (AIN)3 and vulvar (VIN)4 cancer. This statistic highlights the need for better treatment and a cure for HPV. HPV is sometimes passed on to a newborn from the mother during labor. This can result in a rare condition called Recurrent Respiratory Papillomatosis or RRP where growths emerge in the respiratory tract and can even move into the lungs. HPV6 and HPV11 are most closely associated with RRP.

There is no approved product to cure the ~30% of HPV infections that do not clear on their own. Related warts can be removed using a variety of surgical approaches; however, the growths frequently return and the underlying infection persists which can be a risk factor. Genetic tests can be performed to identify the presence and strain of HPV, serving as a screen for individuals most likely to present dysplasia or cancer. If abnormal tissue is identified and treatment is necessary, the most common approaches to remove the growths include cryosurgery, laser therapy and loop electrosurgical excision procedure (LEEP).

Over three million women receive abnormal or unclear PAP smears every year and cervical dysplasia is estimated to affect from 250,000 to 1 million women5 in the United States. For 2019, the NIH anticipates about 13,170 new cases of cervical cancer6 when dysplasia advances to a more serious stage. Prompt treatment of cervical dysplasia has a higher rate of success than treatment after a cancer diagnosis highlighting the importance of early detection and the need for therapies able to reverse the condition.

Inovio HPV Franchise

Inovio recognized the unmet need in HPV-related abnormalities and began its development of VGX-3100, initially targeting cervical dysplasia and later conducting additional studies to expand into related sites including AIN, VIN as well as head and neck cancer. Inovio has achieved ten years of progress in the HPV franchise with its SynCon synthetic vaccine design which uses immunotherapy to treat a broad portfolio of cancers and infectious diseases. The company achieved a major milestone in July 2014 when it announced that VGX-3100 had achieved its primary and secondary efficacy endpoint in a Phase IIb cervical dysplasia trial. The company has continued to advance its candidates and now offers a portfolio of six Phase II programs and one Phase III program in addition to its infectious disease portfolio.

Exhibit III – Immunotherapy Clinical Pipeline7

The cancer indications employ the use of electroporation with the CELLECTRA8 device to deliver plasmids to patients’ cells that manufacture specific antigens in vivo, addressing HPV-related cancers and glioblastoma multiforme (GBM). Inovio’s SynCon DNA design process identifies antigens unique to tumors or other target cells, then it creates a synthetic DNA sequence which can be inserted into a DNA plasmid for delivery via electroporation into cells in the body.

Inovio visually explains its SynCon DNA immunotherapy in a short video highlighting the process of delivering DNA plasmids to muscle cells9. After the plasmids enter the cell, they use cellular machinery to generate antigens which are able to address disease by activating T cells that can target specific epitopes unique to cancerous cells. This method helps break immune tolerance by using multiple tumor specific antigens which direct the T cells to attack the cancer more thoroughly compared to single antigen approaches.

Partnerships and Collaborations

Inovio has distinguished itself through a number of partnerships and collaborations throughout its portfolio. Partners include AstraZeneca which acquired exclusive rights to MEDI0457 (previously INO-3112) for head and neck and other cancers caused by HPV infection, and is studying the drug in combination with its checkpoint inhibitor, durvalumab, in Phase II trials. The deal with AstraZeneca provided Inovio $27.5 million in upfront payment and could generate up to $250 million in milestone payments along with significant royalties once the product is on the market. Regeneron is another collaborator, pairing its PD-1 inhibitor cemiplimab with Inovio’s INO-5401 in GBM. The biotech is also working with QIAGEN N.V. to develop a complementary diagnostic for VGX-3100. The effort was announced in May to create a liquid biopsy-based diagnostic to identify patients likely to benefit from VGX-3100. Approved therapies with accompanying diagnostics demonstrate improved pricing ability with payors, better success rates with patients and higher penetration into the appropriate population.

Fast to Market Products

Inovio has the advantage of an expansive pipeline which provides both near term and long term catalysts. Two of the most important near term drivers are milestones related to the RRP and GBM programs. 2020 will offer a cascade of study events and data readouts for these two indications that can generate value for Inovio shares.

RRP

Recurrent respiratory papillomatosis (RRP) is an HPV-related non-cancerous tumor growth in the human airways caused by HPV types 6 and 11. The growth of the tumor can cause a variety of symptoms, including hoarseness, chronic cough, recurrent pneumonia and difficulty breathing. While not typically associated with cancer, RRP can cause severe morbidity and death if not controlled. It can also spread to the lungs where it can cause respiratory failure.

Exhibit IV – Rendering of Tracheal Papilloma10

RRP is a rare disease that affects an estimated 4.3 per 100,000 children and 1.8 per 100,000 adults11,12. According to data sourced by Inovio, prevalence is about 20,000 and incidence is close to 6,000 cases per year in the United States. These numbers are similar in Europe and prevalence rates are estimated to be similar in China.

Current treatment for RRP is surgery, which may be required multiple times per year in order to clear the recurrent tumor growths and free the airway. Anecdotally, each visit to the surgeon requires two to three days in the hospital and can cost from $40,000 to $50,000. In terms of monetary impact, a successful cure could save $80,000 to $200,000 per year. Even if the treatment only extends the length of time between necessary surgeries, it still can improve patient quality of life and reduce costs to the health care system.

RRP Pilot Study

Inovio conducted a pilot study in two adult patients diagnosed with RRP and positive for HPV 6 in 2016. Prior to treatment, both patients required regular surgery every six months to clear the tumors from the airway. Following treatment with INO-3106 (a precursor to INO-3107)13 the first patient has sustained almost three years without requiring surgery and the other almost two years prior to needing surgery.

Inovio expects to launch a pivotal study in early 2020 and is likely to qualify for expedited status, given RRPs categorization as a rare, orphan disease. An orphan designation will allow for protocol assistance, tax credits, research grants, fee waivers and most importantly a faster path to approval which could allow 3107 to beat 3100 to market. Since RRP also affects children and the study is expected to include pediatric patients, a Rare Pediatric Disease priority review voucher (PRV) may also be granted upon approval. PRVs can be used internally or sold with historical deal values ranging from $68 to $350 million14. INO-3107 may qualify for an abbreviated pathway to commercialization that could help validate the SynCon Technology Platform and the entire Inovio pipeline.

GBM

Glioblastoma multiforme (GBM) is a rare disease but a common type of brain cancer that is notoriously fatal and hard to treat. The cancer is only recognized as grade IV which is very aggressive and most diagnosed patients die within a year. GBM is difficult to treat because the tumor cells are resistant to standard therapies and many drugs have difficulty crossing the blood brain barrier. The brain is susceptible to damage from surgery and other standard of care and only has limited repair capacity presenting additional hurdles to success.

Exhibit V – Image of Glioblastoma WHO Grade IV15

The first signs of GBM may be headaches, seizures, vomiting, vision problems, changes in personality and difficulty speaking. After signs are identified and a condition is suspected, a neurological assessment is given to the patient which examines vision, hearing, balance, coordination, strength and reflexes to narrow down the cause. Next steps include an MRI or CT scan to identify the tumor and a biopsy may also be performed. Standard of care treatment for GBM includes surgery to remove as much of the tumor as possible followed by radiation and chemotherapy, frequently using temozolomide or carmustine. Due to the low survival rate (about 40% at one year) and lack of effective therapies, the FDA is more accepting of developmental therapies and is likely to confer expedited status to promising therapeutic candidates.

GBM Combination Therapy Collaboration

In May of 2017 Inovio and Regeneron announced a collaboration to develop a combination therapy using Inovio’s INO-5401 and INO-9012 in conjunction with Regeneron’s PD-1 inhibitor, cemiplimab, to address GBM. INO-5401 is considered a T cell activating immunotherapy and is a combination of three DNA plasmids16 that will produce three different antigens to activate T cells priming them to recognize cancer cells. It is important to note that PD-1 or PD-L1 checkpoint inhibitors used as monotherapy in past GBM trials did not show any meaningful clinical benefit over standard of care.

The collaborative trial launched in mid-2017 and enrolled 52 patients, reaching its target population three months ahead of schedule in April of this year.

On Friday, November 1, the Society for Immunotherapy of Cancer (SITC) revealed on its website that Inovio’s ongoing Phase I/II GBM trial was accepted as a late-breaking abstract, entitled “An Open-Label, Multi-center Trial of INO-5401 and INO-9012 Delivered by Electroporation (EP) in Combination with Cemiplimab in Subjects with Newly-Diagnosed Glioblastoma (GBM).”

As the company previously indicated on an investor call, Inovio expects to announce interim results for the study, including 6-month progression free survival (PFS) and safety data, followed by 12- and 18-month PFS and Overall Survival (OS) in 2020. The open label, multi-center Phase I/II trial endpoints for INO-5401 include the proportion of adverse events over the course of the study, OS at 18 months and several immuno-oncology related biomarkers. The information presented this week at SITC could provide investors with an early glimpse of GBM data. Favorable results could support an early submission to the FDA as GBM is a difficult cancer with high mortality and few other options. A success here could have wide and favorable implications for Inovio’s platform and other pipeline candidates.

With its impressive pipeline, Inovio has many significant milestones and catalysts evolving over the next 12 months. Below we list the most important of them, with the initial look at INO-5401 in a poster presentation available later this week.

Milestones

‣ SITC Poster Presentation, INO-5401 6-month PFS data for Phase I/II GBM – November 2019

‣ Parker Institute Phase II trial in progress for Prostate Cancer (INO-5151) – November 2019

‣ Report interim data from Zika, MERS & Lassa vaccine clinical trials – 4Q:19 to 1Q:20

‣ Report interim data from Phase II AIN & VIN – 1Q:20

‣ Launch of Pivotal Trial for RRP – 1H:20

‣ Phase III readout (Reveal 1) for Cervical Dysplasia (VGX-3100) – 4Q:20

‣ Report 12 and 18 month OS data for Phase I/II GBM trial – 2Q & 4Q:20

‣ AZN Phase II readout for MEDI0457 in Head & Neck Cancer – Mid-2020 (AZN Dependent)

Summary

Inovio is an established contender in the cancer immunotherapy space. The company’s vision centers on attacking HPV-related cancers using the proprietary SynCon IO approach which allows the patient’s cells to synthesize the antigens the body’s immune system will target. The most advanced asset, VGX-3100, is a Phase III treatment for cervical dysplasia flanked by two related Phase II studies for AIN and VIN. However, two other programs may cross the approval finish line first due to their status as rare diseases. Efforts in RRP and GBM represent exciting advances in these conditions that do not yet have available effective treatments. Inovio anticipates an impressive series of announcements and catalysts over the next year plus that can help clarify the value intrinsic to the company and its immunotherapy platform.

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1. NCI Dictionary of Cancer Terms. National Institute of Health, National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cervical-dysplasia LSIL: Low-grade squamous intraepithelial lesion, or changes characteristic of mild dysplasia. HSIL: High-grade squamous intraepithelial lesion, corresponding to severe precancerous changes.

2. Image source: October 2019 Corporate Presentation. Data sources: US CDC (2018) HPV and Cancer, available at: https://www.cdc.gov/cancer/hpv/statistics/cases.htm(accessed July 22, 2019); SaraiyaM, Unger ER, Thompson TD, Lynch CF, Hernandez BY, LyuCW, SteinauM, Watson M, Wilkinson EJ, HopenhaynC, Copeland G, Cozen W, Peters ES, Huang Y, Saber MS, AltekruseS, Goodman MT; HPV Typing of Cancers Workgroup. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J NatlCancer Inst. 2015 Apr 29;107(6):djv086; Inovio Pharmaceuticals, internal estimates from published data (2015-16, 2017-18); US CDC, personal communication (2015); NCI SEER Cancer Stat Facts: Cervix Uteri, Vulvar, and Anal Cancers --https://seer.cancer.gov/statfacts(accessed 2017-18);*Measured as: Genital Warts –Initial Visits to Physicians’ Offices, United States, 1966-2014. Fig. 47; SchiffmanM, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch PatholLab Med. 2003 Aug;127(8):946-9;US CDC. Genital HPV Infection –Fact Sheet.

3. Anal intraepithelial neoplasia

4. Vulvar intraepithelial neoplasia

5. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Cervical dysplasia is most often seen in women between the ages of 25 and 35. https://www.hopkinsmedicine.org/kimmel_cancer_center/centers/cervical_dysplasia/about_cervical_dysplasia/index.html

6. https://seer.cancer.gov/statfacts/html/cervix.html

7. Source: October 2019 Inovio Corporate Presentation.

8. CELLECTRA is Inovio’s patented electroporation device that employs short electrical pulses to create pores in target cells to deliver synthetic DNA vaccines (plasmids) into the cytoplasm of the cell.

9. Myocytes are targeted for DNA plasmid insertion for cancer therapies and basal cells for infectious disease.

10. CT volume rendering of the upper airway in a person with tracheobronchial papillomatosis (anonymized). February 18, 2019, Nootherone321. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:CT_tracheal_papillomatosis_volume.png

11. Derkay, Craid; Wiatrak, Brian. Recurrent Respiratory Papillomatosis: A Review. The Laryngoscope 118: July 2008.

12. National Organization for Rare Disorders. Recurrent Respiratory Papillomatosis. https://rarediseases.org/rare-diseases/recurrent-respiratory-papillomatosis/

13. INO-3106 targets HPV6, while INO-3107 targets both HPV6 and HPV11.

14. Evaluate Priority Review Voucher history.

15. Gliobastoma (astrocytoma) WHO grade IV - MRI sagittal view, post contrast. 15 year old boy. October 5, 2006. Christaras A. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Glioblastoma_-_MR_sagittal_with_contrast.jpg

16. The three targets include the Wilms tumor gene-1 (WT1) antigen, prostate-specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) antigen.

 
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