On January 13, 2020 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported that Janssen Research & Development, LLC (Janssen) presented data from its Phase III ANDROMEDA (AMY3001) study of subcutaneous (SC) daratumumab utilizing ENHANZE in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) for patients with newly diagnosed light-chain (AL) amyloidosis at the 25th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, Halozyme, JUN 13, 2020, View Source [SID1234561079]). Janssen reported that the study met the primary endpoint of percentage of patients with hematologic complete response. Additional information can be accessed here.

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"We are excited that the subcutaneous formulation of daratumumab utilizing ENHANZE has demonstrated positive results in a potentially new indication addressing an underserved population with limited treatment options," said Dr. Helen Torley.

On June 13, 2020 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the positive results from the VIALE-A (M15-656) trial, which demonstrated that previously-untreated patients with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy treated with venetoclax (VENCLEXTA or VENCLYXTO) plus azacitidine achieved a 34 percent reduction in the risk of death compared to azacitidine in combination with placebo (Hazard Ratio [HR]=0.66 [95 percent CI 0.52-.85], p=0.001) (Press release, AbbVie, JUN 13, 2020, View Source [SID1234561078]).1 Patients receiving the venetoclax combination achieved improved median overall survival (OS) (14.7 months versus 9.6 months in the placebo arm), and 66.4 percent of patients treated with venetoclax plus azacitidine had a composite complete remission (CR + CRi) compared to 28.3 percent treated with azacitidine plus placebo.

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The data set was presented for the first time as late-breaking data during the virtual 25th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (abstract #LB2601).

"Patients living with AML may be too sick to endure chemotherapy, and they face one of the most aggressive types of blood cancer," said Neil Gallagher, M.D., Ph.D., chief medical officer, AbbVie. "The positive results from the VIALE-A study underscore the significant impact venetoclax plus azacitidine can have on improved survival and complete response in a previously-untreated patient population."

The randomized, double-blind, placebo-controlled, Phase 3 VIALE-A trial evaluated the efficacy and safety of venetoclax in combination with azacitidine in patients with AML who are ineligible for standard induction therapy. The study met its primary endpoints of statistically significant improvement of OS and composite complete remission rate (CR + CRi). OS was the sole primary endpoint in the U.S. and U.S. reference countries, and OS and CR + CRi were co-primary endpoints in China, Japan, the European Union (EU) and EU reference countries.

"AML is a challenging blood cancer marked by low survival rates – especially among older patients who are not eligible for intensive induction chemotherapy – which leaves them with few treatment options," said Courtney D. DiNardo, M.D., MSCE, Department of Leukemia, Division of Cancer Medicine at MD Anderson and the lead study investigator. "The VIALE-A results provide further insights in venetoclax to significantly extend overall survival and achieve better response rates than azacitidine alone. Venetoclax in combination with azacitidine is an effective therapeutic approach for previously-untreated AML in patients who cannot withstand chemotherapy."

The study also met secondary endpoints, with the venetoclax combination arm resulting in a CR rate of 36.7 percent, a CR with partial hematologic recovery (CRh) rate of 64.7 percent and a composite complete remission rate (CR + CRi) of 66.4 percent, compared to 17.9 percent CR, 22.8 percent CRh and 28.3 percent CR + CRi in the placebo arm.

The observed safety profile is generally consistent with the known safety profiles of venetoclax combined with azacitidine and the known safety profiles of the two medications alone. The most common (occurring in >10 percent of patients) grade 3/4 adverse events in patients receiving venetoclax plus azacitidine were thrombocytopenia (45 percent), neutropenia (42 percent), febrile neutropenia (42 percent), anemia (26 percent), leukopenia (21 percent), pneumonia (20 percent) and hypokalemia (11 percent).

AML is the most common acute leukemia in the world.2 An estimated 160,000 people are currently living with the disease globally with an incidence rate of 103 new cases per 100,000 people.2 It is also among the most difficult blood cancers to treat.3 Despite advances in available therapies and care, the five-year survival rate for patients diagnosed with AML remains approximately 28 percent.4 AML typically worsens quickly, and due to age and comorbidities, not all patients can tolerate intensive induction chemotherapy.5

In November 2018, AbbVie received accelerated approval in the U.S. for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Approval was also granted in Mexico, Israel, Puerto Rico, Peru, Brazil, Russia, Argentina, Guatemala, Uruguay, Lebanon, Bahrain, Kazakhstan, Panama, Saudi Arabia, Taiwan, Australia, Qatar, United Arab Emirates and Belarus.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the VIALE-A (M15-656) Phase 3 Trial
A total of 433 treatment-naïve, intensive chemotherapy ineligible AML patients were randomized in the double-blind, placebo-controlled Phase 3 VIALE-A trial. The trial was designed to evaluate the efficacy and safety of venetoclax in combination with azacitidine (n=286) compared with placebo in combination with azacitidine (n=145).6

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information7

Uses
VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney or liver problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts; infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact www.medicineassistancetool.org for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here

Indication and Important VENCLYXTO (venetoclax) EU Safety Information8

Indication

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use

TLS, including fatal events, has occurred in patients with previously treated CLL with high tumour burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: moderate or strong CYP3A inhibitors must be used, physicians should refer to the VENCLYXTO summary of product characteristics (SmPC) for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14 and in 15% of patients treated with the combination of venetoclax and in Murano and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

Specific Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

On June 12, 2020 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for GARDASIL9 for the prevention of oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58 (Press release, Merck & Co, JUN 12, 2020, View Source [SID1234607431]). The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The trial is currently underway.

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"At Merck, working to help prevent certain HPV-related cancers has been a priority for more than two decades," said Dr. Alain Luxembourg, director, clinical research, Merck Research Laboratories. "Today’s approval for the prevention of HPV-related oropharyngeal and other head and neck cancers represents an important step in Merck’s mission to help reduce the number of men and women affected by certain HPV-related cancers."

GARDASIL 9 is a vaccine indicated in females 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by human papillomavirus (HPV) Types 16, 18, 31, 33, 45, 52, and 58; cervical, vulvar, vaginal, and anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.

GARDASIL 9 is indicated in males 9 through 45 years of age for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.

GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant].

Both men and women can be at risk for HPV-attributable oropharyngeal cancer; however, this cancer affects men five times more than women.1 For most people, HPV clears on its own. But, for those who don’t clear the virus, it can cause certain cancers. Oropharyngeal cancer can arise as a result of HPV infection in the oropharynx, which includes the soft palate, side and back wall of the throat, tonsils, and back one-third of the tongue. According to a recent model published by the U.S. Centers for Disease Control and Prevention (CDC), HPV-attributable oropharyngeal cancer has surpassed cervical cancer as the most prevalent type of HPV-related cancer in the U.S.1

1 The CDC analyzed data from the U.S. Cancer Statistics (USCS) to assess the incidence of HPV-associated cancers and to estimate the annual number of cancers caused by HPV, overall and by state, during 2012 to 2016.

The estimated number of HPV-attributable cancers was calculated by multiplying the average number of HPV-associated cancers by the percentage of HPV-attributable cancers diagnosed from 1993 to 2005, before HPV vaccination was available in the U.S.

The detection of HPV DNA in an HPV study is not enough to determine that HPV caused the cancer.

Not all cervical and oropharyngeal cancers are caused by HPV.

Important Information About GARDASIL 9

GARDASIL 9 does not eliminate the necessity for vaccine recipients to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended by a healthcare provider.

GARDASIL 9 has not been demonstrated to provide protection against diseases caused by:

HPV types not covered by the vaccine
HPV types to which a person has previously been exposed through sexual activity
Not all vulvar, vaginal, anal, oropharyngeal and other head and neck cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58.

GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is not a treatment for external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; or cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial neoplasia (AIN).

Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.

Select Safety Information for GARDASIL 9

GARDASIL 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant].

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following HPV vaccination. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.

Safety and effectiveness of GARDASIL 9 have not been established in pregnant women.

The most common (≥10%) local and systemic adverse reactions in females were injection-site pain, swelling, erythema, and headache. The most common (≥10%) local and systemic reactions in males were injection-site pain, swelling, and erythema.

The duration of immunity of GARDASIL 9 has not been established.

Dosage and Administration for GARDASIL 9

GARDASIL 9 should be administered intramuscularly in the deltoid or anterolateral area of the thigh.

For individuals 9 through 14 years of age, GARDASIL 9 can be administered using a 2-dose or 3-dose schedule. For the 2-dose schedule, the second dose should be administered 6-12 months after the first dose. If the second dose is administered less than 5 months after the first dose, a third dose should be given at least 4 months after the second dose. For the 3-dose schedule, GARDASIL 9 should be administered at 0, 2 months, and 6 months.
For individuals 15 through 45 years of age, GARDASIL 9 is administered using a 3-dose schedule at 0, 2 months, and 6 months.
About HPV and HPV-related Cancers and Diseases

According to the CDC, an estimated 14 million new HPV infections occur every year in the United States. HPV is so common that 80% of people who are sexually active get HPV at some point in their life. For most people, HPV clears on its own; but for those who don’t clear the virus, it could cause certain cancers and diseases. There is no way to know which people who have HPV will develop cancer or other health problems. GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) helps protect against seven HPV types that cause the majority of HPV-related cancers in the United States. Persistent HPV infection can also lead to pre-cancerous lesions that may require additional follow-up procedures. With the exception of cervical cancer, there is no routinely recommended screening for the detection of HPV-related cancers.

On June 12, 2020 DCprime, the front-runner in the field of relapse vaccines, in collaboration with the University of Bergen, reported the presentation of a novel preclinical animal model tailored for cancer vaccine research at the virtual 25th European Hematology Association (EHA) (Free EHA Whitepaper) Congress (EHA) (Free EHA Whitepaper) (Press release, DCPrime, JUN 12, 2020, View Source [SID1234561871]). The humanized immunocompetent mouse model was applied to evaluate DCprime’s lead product DCP-001 as a standalone vaccine against leukemic cells, and will also enable future evaluation of DCP-001 in combination with chemotherapy or immune modulators. The full abstract and poster are available via the EHA (Free EHA Whitepaper) Meeting’s website.

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"This crucial animal model will be invaluable in advancing our pre-clinical knowledge of DCP-001 and its development could not have been accomplished without the expertise from our partners at the University of Bergen," said Jeroen Rovers, MD, PhD, Chief Medical Officer of DCprime. "We look forward to working closely with Bergen University on future research initiatives as well as within the public-private consortium AML-VACCiN that continues to drive the clinical development of DCP-001 despite the current challenges in clinical practice due to COVID-19."

"We are excited to support DCprime’s novel cancer relapse vaccine strategy as a potential future therapy to efficiently keep hematological cancers in check. Generating a mouse model that supports the xenograft of leukemic cell lines in conjunction with systemic engraftment of a human immune system, has been very instrumental to demonstrate the therapeutic potential of DCP-001 as a cell-based cancer vaccine," commented Professor Bjørn Tore Gjertsen, Department of Clinical Science at the University of Bergen

DCprime’s lead cancer relapse vaccine candidate DCP-001 is generated by transforming a proprietary leukemic cell, DCOne, into a whole cell-based cancer vaccine. Clinical data from a previously concluded phase 1 clinical study that was presented at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2019 demonstrated DCP-001’s potential to prolong relapse-free survival and overall survival as an allogeneic, off-the-shelf cell-based vaccine in the post-remission setting.

DCP-001 is currently being evaluated in the international, multi-center, open-label proof-of-concept study ADVANCE-II with AML patients in complete remission, but with persistent measurable residual disease (MRD). The associated AML-VACCiN consortium receives support from the EU under the Horizon 2020 program. More information can be found at www.amlvaccin.eu.

On June 12, 2020 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported that an oral presentation and three poster presentations of new clinical data and analyses related to imetelstat, the Company’s first-in-class telomerase inhibitor, are now available on Geron’s website as well as to participants of the Virtual Edition of the 25th Annual EHA (Free EHA Whitepaper) Annual Congress (Press release, Geron, JUN 12, 2020, View Source [SID1234561082]).

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Updated Efficacy and Safety Data from IMerge Phase 2 Clinical Trial in Lower Risk Myelodysplastic Syndromes (MDS)

"The EHA (Free EHA Whitepaper) presentation reports encouraging continued durability data from the IMerge Phase 2 clinical trial, including a median duration of 8-week transfusion independence of 20 months, which is the longest duration we have reported to date in this trial, and that 29% of patients were transfusion free for more than one year," said Aleksandra Rizo, M.D., Ph.D., Geron’s Chief Medical Officer. "We expect these data to drive further interest of investigators, which will promote enrollment for the ongoing IMerge Phase 3 clinical trial in lower risk MDS."

Title: Treatment with Imetelstat Provides Durable Transfusion Independence (TI) in Heavily Transfused Non-del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) (Abstract #S183)

The oral presentation reports long-term efficacy and safety data from 38 patients in the IMerge Phase 2 clinical trial, based on a February 4, 2020 cut-off date and a median follow-up of 24 months. IMerge is a two-part Phase 2/3 clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (lower risk MDS), who are relapsed after or refractory to prior treatment with ESAs. The first part of IMerge was designed as a Phase 2, open label, single arm study to assess the efficacy and safety of imetelstat. The primary efficacy endpoint is 8-week TI rate, which is defined as the proportion of patients achieving red blood cell transfusion independence during any consecutive eight weeks since entry into the trial. Secondary endpoints include rate of hematologic improvement-erythroid (HI-E) and duration of TI. Several patients remain on treatment in the IMerge Phase 2 clinical trial.

The conclusions of the oral presentation are as follows:

Meaningful and durable transfusion independence (TI):
° High rates of TI and HI-E: 42% 8-week TI rate and 68% HI-E rate
° Durable TI and HI-E: Median duration of TI is 20 months and median duration of HI-E is 21 months
° TI across multiple patient subtypes: ringed sideroblast positive (RS+) and RS-, high and very high transfusion burden

Potential disease-modifying activity:
° 29% of patients transfusion free for more than 1 year
° 75% of 8-week TI responders had a hemoglobin rise of > 3g/dL from pretreatment level
° Reduction in variant allele frequency (VAF) of SF3B1 mutation correlated with shorter time to TI and duration of TI

No new safety signal identified:
° Reversible cytopenias, without significant clinical consequences were most frequent adverse events
The slide presentation is available on Geron’s website at www.geron.com/r-d/publications.

Ongoing IMerge Phase 3 Clinical Trial

The IMerge Phase 3 clinical trial is a double-blind, randomized, placebo-controlled clinical trial with registration intent. The trial is designed to enroll approximately 170 patients with lower risk transfusion dependent MDS who are relapsed or refractory to an ESA, have not received prior treatment with either a hypomethylating agent (HMA) or lenalidomide and who are non-del(5q). The trial was opened for screening and enrollment in August 2019. As of the end of April 2020, approximately 68% of planned clinical sites for the IMerge Phase 3 trial were open for enrollment. Geron expects to complete patient enrollment by the end of the first quarter of 2021. Under current assumptions, the Company expects top-line results to be available in the second half of 2022.

New Analyses of Data from IMbark Phase 2 Clinical Trial in Intermediate-2 or High-risk Myelofibrosis

"Taken together, we believe the three EHA (Free EHA Whitepaper) poster presentations reporting new analyses of IMbark Phase 2 data substantiate the OS outcome observed in IMbark and indicate potential disease-modifying activity of imetelstat in yet another hematologic indication," said Aleksandra Rizo, M.D., Ph.D., Geron’s Chief Medical Officer. "These analyses also provide further support for our planned Phase 3 clinical trial in refractory MF, which is expected to open for enrollment in the first quarter of 2021."

IMbark was designed as a Phase 2 clinical trial to evaluate two dosing regimens of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every three weeks) in patients with Intermediate-2 or High-risk myelofibrosis (MF) who have relapsed after or are refractory to prior treatment with a janus kinase inhibitor (JAKi). The co-primary efficacy endpoints for IMbark were spleen response rate, defined as the proportion of patients who achieve a reduction of at least 35% in spleen volume as assessed by imaging, and symptom response rate, defined as the proportion of patients who achieve a reduction of at least 50% in Total Symptom Score (TSS), at 24 weeks. Key secondary endpoints were overall survival (OS) and safety.

Title: Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes in Higher-Risk Myelofibrosis (MF) Relapsed/Refractory (R/R) to Janus Kinase Inhibitor Treated with Imetelstat (Abstract #EP1098)

The conclusions of the poster are as follows:

Imetelstat achieved dose- and exposure-dependent reduction of telomerase activity and human reverse transcriptase (hTERT) expression level, demonstrating on-target mechanism of action.
Achieving optimal pharmacodynamic (PD) effect in patients treated with imetelstat is correlated with longer OS, as well spleen and symptom response.
Significant dose-dependent reduction in VAF of JAK2, CALR and MPL mutations were observed, indicating that imetelstat has disease-modifying activity by targeting the underlying MF malignant clones.
Treatment with 9.4mg/kg of imetelstat improved clinical outcomes in patients with short telomeres or high hTERT expression level at baseline. The results are consistent with telomere biology in cancer cells and provide evidence for on-target mechanism of action of imetelstat through telomerase inhibition.
This is the first clinical report to systematically evaluate the mechanism of action based PD effect of imetelstat, and its relationship to exposure and clinical benefits.
The poster presentation is available on Geron’s website at www.geron.com/r-d/publications.

Title: Imetelstat Treatment Results in Clinical Benefits, Including Improved Overall Survival, in Patients with Higher-Risk Triple Negative Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitors (JAKI) (Abstract #1101)

The overall conclusion of the poster is that triple negative (TN) patients who are relapsed/refractory to JAKi and treated with 9.4 mg/kg of imetelstat had better clinical outcomes and prolonged overall survival (OS) compared to non-TN patients, suggesting that imetelstat may improve the poor outcomes expected for TN patients. Additional highlights from the poster include:

With 9.4 mg/kg of imetelstat treatment, clinical response rates were higher in TN vs non-TN pts: spleen response rate was 18.8% in TN vs 7.3% in non-TN; and symptom response was 50.0% in TN vs 24.4% in non-TN patients.
Imetelstat treatment at 9.4 mg/kg resulted in significantly longer median OS of 35.9 months for TN patients compared to 24.6 months for non-TN patients.
A majority (94%) of the TN patients enrolled on the study had grade three fibrosis. Higher rate of bone marrow fibrosis improvement was noted in the TN (50%) vs non-TN (39.1%) patients.
TN patients enrolled on the study had short telomere length and high hTERT expression level at baseline, representing a suitable target population for imetelstat, a first-in-class telomerase inhibitor.
The poster presentation is available on Geron’s website at www.geron.com/r-d/publications.

Title: Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate-2 or High-Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor (Abstract #1107)

The poster reports new analyses of data from all 107 patients in both arms (59 patients in the 9.4 mg/kg arm and 48 patients in the 4.7 mg/kg arm) of the IMbark Phase 2 clinical trial with a data cut-off date of February 19, 2020 and a median follow-up of 41.7 months. As of the data cut-off date, median OS was 28.1 months in the 9.4 mg/kg arm and 19.9 months in the 4.7 mg/kg arm.

The overall conclusion of the poster was that imetelstat showed dose-related improvement in OS in patients who are R/R to JAKi. The survival benefit observed with imetelstat was supported by the trend of correlation with other clinical benefits. Additional highlights from the poster include:

Among 57 patients across both treatment arms that had matching bone marrow samples, 20 patients (35%) had ≥1 degree of bone marrow fibrosis improvement while on study and had a significantly longer OS than those who had worsening bone marrow fibrosis. A similar trend was seen in 29 patients (51%) with stable vs. worsening fibrosis.
Patients who achieved symptom and spleen response at week 24 showed a trend of longer OS compared to patients who did not achieve response.
Transfusion dependency, response to last JAKi, higher baseline neutrophils, lower baseline hemoglobin and platelet values correlated with increased risk of death.
The poster presentation is available on Geron’s website at www.geron.com/r-d/publications.

Planned Phase 3 Clinical Trial in Refractory MF

The planned Phase 3 clinical trial in refractory MF is designed to be an open label 2:1 randomized, controlled trial with registration intent to evaluate imetelstat (9.4 mg/kg administered by intravenous infusion every three weeks) in approximately 320 patients with Intermediate-2 or High-risk MF. Patients eligible for the trial will be required to be refractory to a JAK inhibitor, an inclusion criterion that is planned to be defined as having an inadequate spleen response or symptom response after treatment with a JAK inhibitor for at least six months, including an optimal dose of a JAK inhibitor for at least two months. The control arm is planned to be best available therapy (BAT), excluding JAK inhibitors. The primary efficacy endpoint for the trial is planned to be overall survival (OS). Planned key secondary endpoints include symptom response, spleen response, progression free survival, complete response, partial response, clinical improvement, duration of response, safety, pharmacokinetics, and patient reported outcomes. Under current assumptions, the Company expects to complete patient enrollment in the second half of 2022, to conduct an interim analysis in the first half of 2023 and to conduct a final analysis in the first half of 2024. The final analysis for OS is planned to be conducted after more than 50% of the patients planned to be enrolled in the trial have died. An interim analysis of OS is planned to be conducted after approximately 70% of the total projected number of events for the final analysis have occurred. Both the planned interim and final analyses are event driven and could occur on different timelines than currently expected.

Event with Key Opinion Leaders to Discuss EHA (Free EHA Whitepaper) Presentations

On June 17, 2020, Geron will be hosting a webcasted event with authors from each respective data presentation from the EHA (Free EHA Whitepaper) Annual Congress who will reprise the presentations from EHA (Free EHA Whitepaper). A live, listen-only webcast will be available on the Company’s website at www.geron.com/investors/events. If you are unable to listen to the live call, an archived webcast will be available on the Company’s website for 30 days.

Participants may access the conference call live via telephone by dialing domestically +1 (833) 513-0551 or internationally +1 (647) 689-4209. The conference ID is 1988213.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic myeloid malignancies. Early clinical data suggest imetelstat may have disease-modifying activity through the apoptosis of malignant stem and progenitor cells, which allows potential recovery of normal hematopoiesis. Geron’s imetelstat development program includes two ongoing or planned registration-enabling studies, IMerge, an ongoing Phase 2/3 clinical trial in lower risk myelodysplastic syndromes (MDS), and a planned Phase 3 clinical trial in refractory myelofibrosis (MF) expected to be open for patient screening and enrollment in the first quarter of 2021. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis-stimulating agent and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment.