Anemia

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.

Red blood cells

The European Commission has approved eltrombopag (Revolade) for the treatment of adults with severe aplastic anemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplant.

Eltrombopag is the first therapy approved in the European Union (EU) for this patient population.

The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

Trials of eltrombopag in SAA

The European Commission’s approval is based primarily on results of a phase 2 pilot study (NCT00922883) conducted by the National Heart, Lung and Blood Institute at the National Institutes of Health.

Results from the ongoing study were published in NEJM in 2012 and Blood in 2013. The trial has enrolled 43 patients with SAA who had an insufficient response to at least 1 prior immunosuppressive therapy and who had a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 (range, 17 to 77), and 56% were male. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (n=17) experienced a hematologic response in at least 1 lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow-up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients were also evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

About eltrombopag

Eltrombopag is already approved to treat SAA in the US and Canada. The drug recently gained approval in the US to treat children age 1 and older who have chronic immune thrombocytopenia and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag is approved in more than 100 countries to treat adults with chronic immune thrombocytopenia who have had an inadequate response to or are intolerant of other treatments.

The drug is approved in more than 45 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Eltrombopag is marketed under the brand name Promacta in the US and Revolade in most other countries. For more details on the drug, see the European Medicines Agency’s Summary of Product Characteristics.

Red blood cells

The European Commission has approved eltrombopag (Revolade) for the treatment of adults with severe aplastic anemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplant.

Eltrombopag is the first therapy approved in the European Union (EU) for this patient population.

The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

Trials of eltrombopag in SAA

The European Commission’s approval is based primarily on results of a phase 2 pilot study (NCT00922883) conducted by the National Heart, Lung and Blood Institute at the National Institutes of Health.

Results from the ongoing study were published in NEJM in 2012 and Blood in 2013. The trial has enrolled 43 patients with SAA who had an insufficient response to at least 1 prior immunosuppressive therapy and who had a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 (range, 17 to 77), and 56% were male. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (n=17) experienced a hematologic response in at least 1 lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow-up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients were also evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

About eltrombopag

Eltrombopag is already approved to treat SAA in the US and Canada. The drug recently gained approval in the US to treat children age 1 and older who have chronic immune thrombocytopenia and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag is approved in more than 100 countries to treat adults with chronic immune thrombocytopenia who have had an inadequate response to or are intolerant of other treatments.

The drug is approved in more than 45 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Eltrombopag is marketed under the brand name Promacta in the US and Revolade in most other countries. For more details on the drug, see the European Medicines Agency’s Summary of Product Characteristics.

Red blood cells

The European Commission has approved eltrombopag (Revolade) for the treatment of adults with severe aplastic anemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplant.

Eltrombopag is the first therapy approved in the European Union (EU) for this patient population.

The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

Trials of eltrombopag in SAA

The European Commission’s approval is based primarily on results of a phase 2 pilot study (NCT00922883) conducted by the National Heart, Lung and Blood Institute at the National Institutes of Health.

Results from the ongoing study were published in NEJM in 2012 and Blood in 2013. The trial has enrolled 43 patients with SAA who had an insufficient response to at least 1 prior immunosuppressive therapy and who had a platelet count of 30 x 10⁹/L or less.

At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, the absolute neutrophil count was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L.

Patients had a median age of 45 (range, 17 to 77), and 56% were male. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies.

Patients received eltrombopag at an initial dose of 50 mg once daily for 2 weeks. The dose increased over 2-week periods to a maximum of 150 mg once daily.

The study’s primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment. Treatment was discontinued after 16 weeks in patients who did not exhibit a hematologic response.

Forty percent of patients (n=17) experienced a hematologic response in at least 1 lineage—platelets, red blood cells (RBCs), or white blood cells—after week 12.

In the extension phase of the study, 8 patients achieved a multilineage response. Four of these patients subsequently tapered off treatment and maintained the response. The median follow-up was 8.1 months (range, 7.2 to 10.6 months).

Ninety-one percent of patients were platelet-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require platelet transfusions for a median of 200 days (range, 8 to 1096 days).

Eighty-six percent of patients were RBC-transfusion-dependent at baseline. Patients who responded to eltrombopag did not require RBC transfusions for a median of 208 days (range, 15 to 1082 days).

The most common adverse events (≥20%) associated with eltrombopag were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).

Patients were also evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality after treatment, including 5 patients who had complex changes in chromosome 7.

Patients who develop new cytogenetic abnormalities while on eltrombopag may need to be taken off treatment.

About eltrombopag

Eltrombopag is already approved to treat SAA in the US and Canada. The drug recently gained approval in the US to treat children age 1 and older who have chronic immune thrombocytopenia and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag is approved in more than 100 countries to treat adults with chronic immune thrombocytopenia who have had an inadequate response to or are intolerant of other treatments.

The drug is approved in more than 45 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Eltrombopag is marketed under the brand name Promacta in the US and Revolade in most other countries. For more details on the drug, see the European Medicines Agency’s Summary of Product Characteristics.

Nocturnal and awake oxygen saturations are higher in children whose sickle cell disease (SCD) is treated with hydroxyurea, according to the results of a study by Dr. Indra Narang of the Hospital for Sick Children in Toronto and her colleagues.

“Improving Sa_O2 [oxygen saturation] may be an important mechanism of action of hydroxyurea therapy. As such, improving Sa_O2 across the severity spectrum of SCD may be beneficial in decreasing SCD morbidities with an overall improvement in long-term health,” the researchers wrote.

Courtesy Wikimedia Commons/National Human Genome Research Institute/Creative Commons License

Sickle cell disease is characterized by development of rigid and sickled cells when deoxygenated, which may result in vasoocclusive injury to organs. Hydroxyurea enhances the production of fetal hemoglobin and can lead to less acute chest syndrome and vasoocclusive crises. Furthermore, children with sickle cell disease have a high prevalence of obstructive sleep apnea, which is associated with nocturnal desaturations and may be related to morbidity in SCD.

To evaluate the role of hydroxyurea in nocturnal oxygen saturations in pediatric patients, the researchers conducted a cross-sectional review of pediatric SCD patients referred for polysomnograms at the Hospital for Sick Children in Toronto from May 2007 to May 2014. Polysomnography data were analyzed on 37 children with SCD on hydroxyurea and matched with 104 children with SCD not treated with hydroxyurea. SA_O2 was assessed using the Masimo oximeter (Ann Am Thorac Soc. 2015 July;12[7]1044-9).

Obstructive sleep apnea was found in 38% (n = 14) of subjects treated with hydroxyurea versus 52% (n = 54) in the nonhydroxyurea group. In the hydroxyurea group, the median obstructive apnea-hypopnea index was 0.9 events/hr vs. 1.9 events/hr in the nonhydroxyurea group, Dr. Narang and her associates reported.

Compared with the nonhydroxyurea SCD group, the hydroxyurea SCD group had significantly higher median awake (98.6% vs. 96.2%; P less than .0001) and sleep oxygen saturations (98.4% vs. 96.1%; P less than .0001). Likewise, treatment with hydroxyurea was associated with a significantly higher sleep oxygen saturation nadir when compared with the nonhydroxyurea group (91.4% vs. 85%; P = .0002), the investigators said.

Finally, treatment with hydroxyurea was associated with higher hemoglobin levels than no hydroxyurea treatment (P less than .0001) and the hemoglobin levels significantly correlated with sleep, awake, and lowest nocturnal oxygen saturation (P less than .0001).

The authors said that they had no conflicts to disclose.

Nocturnal and awake oxygen saturations are higher in children whose sickle cell disease (SCD) is treated with hydroxyurea, according to the results of a study by Dr. Indra Narang of the Hospital for Sick Children in Toronto and her colleagues.

“Improving Sa_O2 [oxygen saturation] may be an important mechanism of action of hydroxyurea therapy. As such, improving Sa_O2 across the severity spectrum of SCD may be beneficial in decreasing SCD morbidities with an overall improvement in long-term health,” the researchers wrote.

Courtesy Wikimedia Commons/National Human Genome Research Institute/Creative Commons License

Sickle cell disease is characterized by development of rigid and sickled cells when deoxygenated, which may result in vasoocclusive injury to organs. Hydroxyurea enhances the production of fetal hemoglobin and can lead to less acute chest syndrome and vasoocclusive crises. Furthermore, children with sickle cell disease have a high prevalence of obstructive sleep apnea, which is associated with nocturnal desaturations and may be related to morbidity in SCD.

To evaluate the role of hydroxyurea in nocturnal oxygen saturations in pediatric patients, the researchers conducted a cross-sectional review of pediatric SCD patients referred for polysomnograms at the Hospital for Sick Children in Toronto from May 2007 to May 2014. Polysomnography data were analyzed on 37 children with SCD on hydroxyurea and matched with 104 children with SCD not treated with hydroxyurea. SA_O2 was assessed using the Masimo oximeter (Ann Am Thorac Soc. 2015 July;12[7]1044-9).

Obstructive sleep apnea was found in 38% (n = 14) of subjects treated with hydroxyurea versus 52% (n = 54) in the nonhydroxyurea group. In the hydroxyurea group, the median obstructive apnea-hypopnea index was 0.9 events/hr vs. 1.9 events/hr in the nonhydroxyurea group, Dr. Narang and her associates reported.

Compared with the nonhydroxyurea SCD group, the hydroxyurea SCD group had significantly higher median awake (98.6% vs. 96.2%; P less than .0001) and sleep oxygen saturations (98.4% vs. 96.1%; P less than .0001). Likewise, treatment with hydroxyurea was associated with a significantly higher sleep oxygen saturation nadir when compared with the nonhydroxyurea group (91.4% vs. 85%; P = .0002), the investigators said.

Finally, treatment with hydroxyurea was associated with higher hemoglobin levels than no hydroxyurea treatment (P less than .0001) and the hemoglobin levels significantly correlated with sleep, awake, and lowest nocturnal oxygen saturation (P less than .0001).

The authors said that they had no conflicts to disclose.

Nocturnal and awake oxygen saturations are higher in children whose sickle cell disease (SCD) is treated with hydroxyurea, according to the results of a study by Dr. Indra Narang of the Hospital for Sick Children in Toronto and her colleagues.

“Improving Sa_O2 [oxygen saturation] may be an important mechanism of action of hydroxyurea therapy. As such, improving Sa_O2 across the severity spectrum of SCD may be beneficial in decreasing SCD morbidities with an overall improvement in long-term health,” the researchers wrote.

Courtesy Wikimedia Commons/National Human Genome Research Institute/Creative Commons License

Sickle cell disease is characterized by development of rigid and sickled cells when deoxygenated, which may result in vasoocclusive injury to organs. Hydroxyurea enhances the production of fetal hemoglobin and can lead to less acute chest syndrome and vasoocclusive crises. Furthermore, children with sickle cell disease have a high prevalence of obstructive sleep apnea, which is associated with nocturnal desaturations and may be related to morbidity in SCD.

To evaluate the role of hydroxyurea in nocturnal oxygen saturations in pediatric patients, the researchers conducted a cross-sectional review of pediatric SCD patients referred for polysomnograms at the Hospital for Sick Children in Toronto from May 2007 to May 2014. Polysomnography data were analyzed on 37 children with SCD on hydroxyurea and matched with 104 children with SCD not treated with hydroxyurea. SA_O2 was assessed using the Masimo oximeter (Ann Am Thorac Soc. 2015 July;12[7]1044-9).

Obstructive sleep apnea was found in 38% (n = 14) of subjects treated with hydroxyurea versus 52% (n = 54) in the nonhydroxyurea group. In the hydroxyurea group, the median obstructive apnea-hypopnea index was 0.9 events/hr vs. 1.9 events/hr in the nonhydroxyurea group, Dr. Narang and her associates reported.

Compared with the nonhydroxyurea SCD group, the hydroxyurea SCD group had significantly higher median awake (98.6% vs. 96.2%; P less than .0001) and sleep oxygen saturations (98.4% vs. 96.1%; P less than .0001). Likewise, treatment with hydroxyurea was associated with a significantly higher sleep oxygen saturation nadir when compared with the nonhydroxyurea group (91.4% vs. 85%; P = .0002), the investigators said.

Finally, treatment with hydroxyurea was associated with higher hemoglobin levels than no hydroxyurea treatment (P less than .0001) and the hemoglobin levels significantly correlated with sleep, awake, and lowest nocturnal oxygen saturation (P less than .0001).

The authors said that they had no conflicts to disclose.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

Genome testing

Photo courtesy of NIGMS

Investigators say they have identified mutations that cause Fanconi anemia and, in the process, gained new insight into interstrand crosslink (ICL) repair.

The researchers studied two patients who had Fanconi anemia with no known genetic cause.

Genomic sequencing revealed that one patient had a mutation in RAD51, and the other had mutations in UBE2T.

These genes—and others linked to Fanconi anemia in previous studies—contribute to ICL repair, which fixes a misplaced attachment between two strands of DNA.

Caused by chemical agents, ICLs block the replication of DNA, making it impossible for cells to accurately copy their genomes as they divide. The ICL repair process uses multiple enzymes that cut away the connection between the DNA strands, freeing them up and allowing the cells to grow.

The genome is at constant risk of forming ICLs, and defects in the ICL repair pathway can produce a constellation of symptoms associated with Fanconi anemia—a predisposition to cancer, bone marrow failure, infertility, and developmental defects.

Via two different studies, Agata Smogorzewska, MD, PhD, of The Rockefeller University in New York, New York, and her colleagues unearthed new discoveries relating to the disease and the pathway.

“Our work began, as it often does, with samples and histories from patients,” Dr Smogorzewska said. “In these cases, we had two patients who each represented a sort of mystery. They had symptoms of Fanconi anemia but no genetic cause yet identified.”

With the RAD51 research, which was published in Molecular Cell, the investigators set out to determine the cause of the Fanconi anemia-like symptoms in a girl in the university’s International Fanconi Anemia Registry.

When they sequenced the protein-coding genes in her genome, the researchers found a mutation in one of two copies of the RAD51 gene.

The RAD1 protein was already known to be important for another DNA repair process—homologous recombination, in which a missing section of DNA is replaced using its sister strand as a template. Homologous recombination is thought to be used during the last step of ICL repair, after the crosslink has been cut.

Because only one copy of the RAD51 gene was partially defective, the patient’s cells could still perform homologous recombination but not ICL repair.

To show that the defective copy of the RAD51 gene was indeed responsible for the patient’s symptoms, the investigators genetically engineered the girl’s own cells to remove the defect, which restored their ability to fix ICLs.

Further experiments on the patient’s cells led the researchers to suspect that RAD51 plays a role outside of homologous recombination, by tamping down the activity of two enzymes that degrade the DNA at the ICL. When RAD51 is defective, these enzymes—DNA2 and WRN—become overly destructive.

With the UBE2T study, published in Cell Reports, the investigators analyzed genomic data from another patient in the International Fanconi Anemia Registry.

They found compound heterozygous mutations in UBE2T—a large genomic deletion in the paternally derived allele and a large duplication in the maternally derived allele.

While it was already known that UBE2T is involved in activating ICL repair, the researchers said the discovery that these mutations could produce Fanconi anemia revealed that UBE2T is an irreplaceable player in the pathway.

“Although we have discovered new causes for this devastating but very rare genetic disease, the implications of this work go much further,” Dr Smogorzewska said.

“By identifying new disruptions to this repair pathway, we can better understand the mechanisms of an event that is crucial to every cell division—a process that occurs constantly within the human body throughout a lifetime.”

Genome testing

Photo courtesy of NIGMS

Investigators say they have identified mutations that cause Fanconi anemia and, in the process, gained new insight into interstrand crosslink (ICL) repair.

The researchers studied two patients who had Fanconi anemia with no known genetic cause.

Genomic sequencing revealed that one patient had a mutation in RAD51, and the other had mutations in UBE2T.

These genes—and others linked to Fanconi anemia in previous studies—contribute to ICL repair, which fixes a misplaced attachment between two strands of DNA.

Caused by chemical agents, ICLs block the replication of DNA, making it impossible for cells to accurately copy their genomes as they divide. The ICL repair process uses multiple enzymes that cut away the connection between the DNA strands, freeing them up and allowing the cells to grow.

The genome is at constant risk of forming ICLs, and defects in the ICL repair pathway can produce a constellation of symptoms associated with Fanconi anemia—a predisposition to cancer, bone marrow failure, infertility, and developmental defects.

Via two different studies, Agata Smogorzewska, MD, PhD, of The Rockefeller University in New York, New York, and her colleagues unearthed new discoveries relating to the disease and the pathway.

“Our work began, as it often does, with samples and histories from patients,” Dr Smogorzewska said. “In these cases, we had two patients who each represented a sort of mystery. They had symptoms of Fanconi anemia but no genetic cause yet identified.”

With the RAD51 research, which was published in Molecular Cell, the investigators set out to determine the cause of the Fanconi anemia-like symptoms in a girl in the university’s International Fanconi Anemia Registry.

When they sequenced the protein-coding genes in her genome, the researchers found a mutation in one of two copies of the RAD51 gene.

The RAD1 protein was already known to be important for another DNA repair process—homologous recombination, in which a missing section of DNA is replaced using its sister strand as a template. Homologous recombination is thought to be used during the last step of ICL repair, after the crosslink has been cut.

Because only one copy of the RAD51 gene was partially defective, the patient’s cells could still perform homologous recombination but not ICL repair.

To show that the defective copy of the RAD51 gene was indeed responsible for the patient’s symptoms, the investigators genetically engineered the girl’s own cells to remove the defect, which restored their ability to fix ICLs.

Further experiments on the patient’s cells led the researchers to suspect that RAD51 plays a role outside of homologous recombination, by tamping down the activity of two enzymes that degrade the DNA at the ICL. When RAD51 is defective, these enzymes—DNA2 and WRN—become overly destructive.

With the UBE2T study, published in Cell Reports, the investigators analyzed genomic data from another patient in the International Fanconi Anemia Registry.

They found compound heterozygous mutations in UBE2T—a large genomic deletion in the paternally derived allele and a large duplication in the maternally derived allele.

While it was already known that UBE2T is involved in activating ICL repair, the researchers said the discovery that these mutations could produce Fanconi anemia revealed that UBE2T is an irreplaceable player in the pathway.

“Although we have discovered new causes for this devastating but very rare genetic disease, the implications of this work go much further,” Dr Smogorzewska said.

“By identifying new disruptions to this repair pathway, we can better understand the mechanisms of an event that is crucial to every cell division—a process that occurs constantly within the human body throughout a lifetime.”

Genome testing

Photo courtesy of NIGMS

Investigators say they have identified mutations that cause Fanconi anemia and, in the process, gained new insight into interstrand crosslink (ICL) repair.

The researchers studied two patients who had Fanconi anemia with no known genetic cause.

Genomic sequencing revealed that one patient had a mutation in RAD51, and the other had mutations in UBE2T.

These genes—and others linked to Fanconi anemia in previous studies—contribute to ICL repair, which fixes a misplaced attachment between two strands of DNA.

Caused by chemical agents, ICLs block the replication of DNA, making it impossible for cells to accurately copy their genomes as they divide. The ICL repair process uses multiple enzymes that cut away the connection between the DNA strands, freeing them up and allowing the cells to grow.

The genome is at constant risk of forming ICLs, and defects in the ICL repair pathway can produce a constellation of symptoms associated with Fanconi anemia—a predisposition to cancer, bone marrow failure, infertility, and developmental defects.

Via two different studies, Agata Smogorzewska, MD, PhD, of The Rockefeller University in New York, New York, and her colleagues unearthed new discoveries relating to the disease and the pathway.

“Our work began, as it often does, with samples and histories from patients,” Dr Smogorzewska said. “In these cases, we had two patients who each represented a sort of mystery. They had symptoms of Fanconi anemia but no genetic cause yet identified.”

With the RAD51 research, which was published in Molecular Cell, the investigators set out to determine the cause of the Fanconi anemia-like symptoms in a girl in the university’s International Fanconi Anemia Registry.

When they sequenced the protein-coding genes in her genome, the researchers found a mutation in one of two copies of the RAD51 gene.

The RAD1 protein was already known to be important for another DNA repair process—homologous recombination, in which a missing section of DNA is replaced using its sister strand as a template. Homologous recombination is thought to be used during the last step of ICL repair, after the crosslink has been cut.

Because only one copy of the RAD51 gene was partially defective, the patient’s cells could still perform homologous recombination but not ICL repair.

To show that the defective copy of the RAD51 gene was indeed responsible for the patient’s symptoms, the investigators genetically engineered the girl’s own cells to remove the defect, which restored their ability to fix ICLs.

Further experiments on the patient’s cells led the researchers to suspect that RAD51 plays a role outside of homologous recombination, by tamping down the activity of two enzymes that degrade the DNA at the ICL. When RAD51 is defective, these enzymes—DNA2 and WRN—become overly destructive.

With the UBE2T study, published in Cell Reports, the investigators analyzed genomic data from another patient in the International Fanconi Anemia Registry.

They found compound heterozygous mutations in UBE2T—a large genomic deletion in the paternally derived allele and a large duplication in the maternally derived allele.

While it was already known that UBE2T is involved in activating ICL repair, the researchers said the discovery that these mutations could produce Fanconi anemia revealed that UBE2T is an irreplaceable player in the pathway.

“Although we have discovered new causes for this devastating but very rare genetic disease, the implications of this work go much further,” Dr Smogorzewska said.

“By identifying new disruptions to this repair pathway, we can better understand the mechanisms of an event that is crucial to every cell division—a process that occurs constantly within the human body throughout a lifetime.”

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to OMS721 for the treatment of atypical hemolytic uremic syndrome (aHUS).

OMS721 is a monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a key regulator of the lectin pathway of the complement system.

The FDA previously granted OMS721 orphan designation for the prevention of thrombotic microangiopathies (TMAs).

Omeros Corporation, the company developing OMS721, has released results from a phase 1 trial of the drug in healthy subjects and an ongoing phase 2 trial in patients with TMAs, including aHUS.

Early positive responses in the phase 2 trial prompted the initiation of a compassionate use program for OMS721 to allow extended treatment of 2 patients who had completed 4 weeks of dosing.

Phase 1 results

In the phase 1 trial of healthy subjects, OMS721 was well tolerated and prompted a high degree of sustained lectin pathway inhibition, according to researchers.

Seven cohorts of subjects received OMS721 or placebo by either subcutaneous injection or intravenous infusion at increasing dose levels. The researchers observed no drug-related adverse events and no clinically significant abnormalities on laboratory tests or electrocardiograms.

At the highest dose evaluated, both routes of administration prompted inhibition of the lectin pathway and achieved the pharmacologic target of sustained inhibition for at least a week.

Phase 2 results and compassionate use

In the ongoing phase 2 study, all patients are receiving OMS721. The researchers said they have observed treatment-related, clinically meaningful improvements in disease markers among the patients treated thus far.

The first cohort in this trial consisted of 3 aHUS patients treated with the lowest dose of OMS721. All 3 patients had improvements in platelet counts after treatment. Serum haptoglobin improved in 2 patients, normalizing in 1.

Serum lactate dehydrogenase levels remained normal in 1 patient, substantially decreased to close to the normal range in another, and remained elevated in the third. Creatinine levels in the 1 patient with independent renal function improved.

One patient was taken off the trial because of a serious adverse event—a localized inflammatory response often related to certain types of infections, one of which the patient previously had for 3 years while on immunosuppressive therapy. All data to date indicate no active infection in this patient.

The patient relapsed after stopping OMS721 treatment. No other significant safety issues were observed in this trial or the phase 1 trial.

The other 2 aHUS patients in this cohort continue to receive OMS721 as part of a compassionate use program. Based on their improvements in disease markers, an investigator requested that Omeros continue to provide OMS721 to these patients.

Following European regulatory approval, Omeros released the shipment of OMS721 so these patients could continue treatment beyond the period that was initially planned for the phase 2 study.

About fast track and orphan designation

The FDA’s fast track program facilitates the development of drugs intended to treat serious or life-threatening conditions and that have the potential to address unmet medical needs. Fast track status affords the company developing a drug greater access to the FDA in order to expedite the drug’s development, review, and potential approval.

Many drugs that receive fast track designation also receive priority review, and their new drug applications may be accepted by the FDA as a rolling submission, in which portions of an application are reviewed before the complete application is submitted. Priority review and rolling submission can each provide further acceleration of the FDA’s approval process.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides a drug’s developer with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to OMS721 for the treatment of atypical hemolytic uremic syndrome (aHUS).

OMS721 is a monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a key regulator of the lectin pathway of the complement system.

The FDA previously granted OMS721 orphan designation for the prevention of thrombotic microangiopathies (TMAs).

Omeros Corporation, the company developing OMS721, has released results from a phase 1 trial of the drug in healthy subjects and an ongoing phase 2 trial in patients with TMAs, including aHUS.

Early positive responses in the phase 2 trial prompted the initiation of a compassionate use program for OMS721 to allow extended treatment of 2 patients who had completed 4 weeks of dosing.

Phase 1 results

In the phase 1 trial of healthy subjects, OMS721 was well tolerated and prompted a high degree of sustained lectin pathway inhibition, according to researchers.

Seven cohorts of subjects received OMS721 or placebo by either subcutaneous injection or intravenous infusion at increasing dose levels. The researchers observed no drug-related adverse events and no clinically significant abnormalities on laboratory tests or electrocardiograms.

At the highest dose evaluated, both routes of administration prompted inhibition of the lectin pathway and achieved the pharmacologic target of sustained inhibition for at least a week.

Phase 2 results and compassionate use

In the ongoing phase 2 study, all patients are receiving OMS721. The researchers said they have observed treatment-related, clinically meaningful improvements in disease markers among the patients treated thus far.

The first cohort in this trial consisted of 3 aHUS patients treated with the lowest dose of OMS721. All 3 patients had improvements in platelet counts after treatment. Serum haptoglobin improved in 2 patients, normalizing in 1.

Serum lactate dehydrogenase levels remained normal in 1 patient, substantially decreased to close to the normal range in another, and remained elevated in the third. Creatinine levels in the 1 patient with independent renal function improved.

One patient was taken off the trial because of a serious adverse event—a localized inflammatory response often related to certain types of infections, one of which the patient previously had for 3 years while on immunosuppressive therapy. All data to date indicate no active infection in this patient.

The patient relapsed after stopping OMS721 treatment. No other significant safety issues were observed in this trial or the phase 1 trial.

The other 2 aHUS patients in this cohort continue to receive OMS721 as part of a compassionate use program. Based on their improvements in disease markers, an investigator requested that Omeros continue to provide OMS721 to these patients.

Following European regulatory approval, Omeros released the shipment of OMS721 so these patients could continue treatment beyond the period that was initially planned for the phase 2 study.

About fast track and orphan designation

The FDA’s fast track program facilitates the development of drugs intended to treat serious or life-threatening conditions and that have the potential to address unmet medical needs. Fast track status affords the company developing a drug greater access to the FDA in order to expedite the drug’s development, review, and potential approval.

Many drugs that receive fast track designation also receive priority review, and their new drug applications may be accepted by the FDA as a rolling submission, in which portions of an application are reviewed before the complete application is submitted. Priority review and rolling submission can each provide further acceleration of the FDA’s approval process.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides a drug’s developer with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to OMS721 for the treatment of atypical hemolytic uremic syndrome (aHUS).

OMS721 is a monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a key regulator of the lectin pathway of the complement system.

The FDA previously granted OMS721 orphan designation for the prevention of thrombotic microangiopathies (TMAs).

Omeros Corporation, the company developing OMS721, has released results from a phase 1 trial of the drug in healthy subjects and an ongoing phase 2 trial in patients with TMAs, including aHUS.

Early positive responses in the phase 2 trial prompted the initiation of a compassionate use program for OMS721 to allow extended treatment of 2 patients who had completed 4 weeks of dosing.

Phase 1 results

In the phase 1 trial of healthy subjects, OMS721 was well tolerated and prompted a high degree of sustained lectin pathway inhibition, according to researchers.

Seven cohorts of subjects received OMS721 or placebo by either subcutaneous injection or intravenous infusion at increasing dose levels. The researchers observed no drug-related adverse events and no clinically significant abnormalities on laboratory tests or electrocardiograms.

At the highest dose evaluated, both routes of administration prompted inhibition of the lectin pathway and achieved the pharmacologic target of sustained inhibition for at least a week.

Phase 2 results and compassionate use

In the ongoing phase 2 study, all patients are receiving OMS721. The researchers said they have observed treatment-related, clinically meaningful improvements in disease markers among the patients treated thus far.

The first cohort in this trial consisted of 3 aHUS patients treated with the lowest dose of OMS721. All 3 patients had improvements in platelet counts after treatment. Serum haptoglobin improved in 2 patients, normalizing in 1.

Serum lactate dehydrogenase levels remained normal in 1 patient, substantially decreased to close to the normal range in another, and remained elevated in the third. Creatinine levels in the 1 patient with independent renal function improved.

One patient was taken off the trial because of a serious adverse event—a localized inflammatory response often related to certain types of infections, one of which the patient previously had for 3 years while on immunosuppressive therapy. All data to date indicate no active infection in this patient.

The patient relapsed after stopping OMS721 treatment. No other significant safety issues were observed in this trial or the phase 1 trial.

The other 2 aHUS patients in this cohort continue to receive OMS721 as part of a compassionate use program. Based on their improvements in disease markers, an investigator requested that Omeros continue to provide OMS721 to these patients.

Following European regulatory approval, Omeros released the shipment of OMS721 so these patients could continue treatment beyond the period that was initially planned for the phase 2 study.

About fast track and orphan designation

The FDA’s fast track program facilitates the development of drugs intended to treat serious or life-threatening conditions and that have the potential to address unmet medical needs. Fast track status affords the company developing a drug greater access to the FDA in order to expedite the drug’s development, review, and potential approval.

Many drugs that receive fast track designation also receive priority review, and their new drug applications may be accepted by the FDA as a rolling submission, in which portions of an application are reviewed before the complete application is submitted. Priority review and rolling submission can each provide further acceleration of the FDA’s approval process.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides a drug’s developer with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.