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Ropeginterferon Alfa-2b Leads to More Durable Responses Than Hydroxyurea in PV
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FRIDAY, MAY 1, 2020
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Patients with polycythemia vera were more likely to achieve durable long-term hematologic response with ropeginterferon alfa-2b than the standard cytoreductive therapy hydroxyurea, according to results from the phase III PROUD-PV trial and its extension study (CONTINUATION-PV). The results, which were published in Lancet Hematology, ¡§suggest that ropeginterferon alfa-2b can be considered as firstline cytoreductive therapy instead of hydroxyurea,¡¨ according to lead author Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and colleagues.
®Ú¾Ú¶ø¦a§Qºû¤]¯Ç¤j¾ÇªºHeinz GisslingerÂå¾Ç³Õ¤h¤Î¨ä¦P¨Æ´£¨ì¡G®Ú¾ÚÁ{§É¤T´Á¸ÕÅçPROUD-PV¤ÎCONTI-PVªº¬ã¨sµ²ªGÅã¥Ü¡A¬Û¸û©ó¼Ð·Çªº²Ó­M´î·ÀÀøªkHU¡AÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101¦bPV¯f±wªºªvÀø¤W§ó¦³¥i¯àÀò±o§óªø®Äªºªø´Á¦å²G¾Ç¤ÏÀ³¡A³o¶µµ²ªGµoªí¦bLancet Hematology¤W¡A«ØijÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101À³³Qµø¬°²Ó­M´î·ÀÀøªk¤@½u¥ÎÃĨú¥NHU¡C

PROUD-PV enrolled 306 adult patients with early-stage polycythemia vera, defined as no history of cytoreductive therapy use or less than 3 years of prior hydroxyurea use. After 1 year, patients could choose to enter the extension part of the trial, CONTINUATION-PV.
Á{§É¤T´Á¸ÕÅçPROUD-PV©Û¶Ò¤F306¦W¦­´ÁPVªº¯f±w¡A¯f±w©w¸q¬°µL²Ó­M´î·ÀÀøªkªvÀø¥v©Î¥ý«e¨Ï¥ÎHUªvÀø¤Ö©ó3¦~¡C¦b°Ñ»PÁ{§É¸ÕÅç¤@¦~«á¡A¯f±w¥i¥H¿ï¾Ü¶i¤J©µ¦ù©Ê¸ÕÅçCONTINUATION-PV¡C

In PROUD-PV, the primary endpoint was noninferiority of ropeginterferon alfa-2b versus hydroxyurea in terms of achievement of complete hematologic response with normal spleen size (defined as a longitudinal diameter of ≤12 cm in women and ≤13 cm in men) assessed at 12 months.
¦bPROUD-PVÁ{§É¸ÕÅç¡A¦b¥D­nÁ{§ÉÀø®Ä«ü¼Ð¥]¬A12­Ó¤ëªº§¹¥þ¦å²G¾Ç¤ÏÀ³»P¥¿±`µÊŦ¤j¤p¡]©w¸q¬°¤k©ÊµÊŦ¤j¤p≤12cm¡A¨k©ÊµÊŦ¤j¤p≤13cm¡^¤è­±¡AÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101¬Û¸û©óHU§e²{«D¦H©Ê¡C

For CONTINUATION-PV, co-primary endpoints included achievement of complete hematologic response with spleen size normalization, as well as improved disease burden. The latter endpoint was assessed by clinical resolution or improvements in splenomegaly, microvascular disturbances, pruritus, and headache.
¦b©µ¦ù©Ê¸ÕÅçCONTI-PV³¡¤À¡A¥D­nÀø®Ä²×ÂI¥]¬A§¹¥þ¦å²G¾Ç¤ÏÀ³©M¥¿±`µÊŦ¤j¤p¡A¥H¤Î§ïµ½¯e¯f­t¾á³¡¤À¡C³Ì«á¤@¶µªºµû¦ô¥]§tµÊ¸~¤j¡B·L¦åºÞ»Ùê¡Bæ±Äo©MÀYµhªº§ïµ½¡C

A total of 257 patients (median age = 60 years; range = 21-85) in the PROUD-PV trial were randomized (1:1) to receive either:
¦bÁ{§É¤T´Á¸ÕÅçPROUD-PV¸ÕÅ礤¡A¦@¦³257¦W¯f±w³QÀH¾÷¤À°t±µ¨ü¥H¤UªvÀø¡G
•subcutaneous ropeginterferon alfa-2b at a starting dose of 100 £gg, administered every 2 weeks (n=127)
127¦W¯f±w³Q¤À°t¨ì¨Ï¥ÎÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101ªvÀø¡A°_©l¾¯¶q¬°100£gg¡A¨C2¶gµ¹ÃĤ@¦¸¡C
•oral hydroxyurea 500 mg/day (n=127)
127¦W¯f±w³Q¤À°t¨ì¤fªA¥ÎÃÄHU¨C¤Ñ500 mg

A total of 171 patients chose to enter the CONTINUATION-PV extension trial.
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Overall, the median follow-up periods for each treatment were 182.1 weeks (interquartile range [IQR] = 166.3-201.7) in the ropeginterferon alfa-2b group and 164.5 weeks (IQR=144.4-169.3) in the hydroxyurea group.
¾ãÅé¦Ó¨¥¡AÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101²ÕªvÀø¤¤¦ì¼Æ¬°182.1¶g¡AHU²Õ¬°164.5¶g

In PROUD-PV, after 1 year of treatment, approximately 21% of patients treated with ropeginterferon alfa-2b and 28% of patients treated with standard therapy met the primary endpoint of complete hematologic response with normal spleen size. The authors concluded that in the first year, ropeginterferon alfa-2b failed to show noninferiority to hydroxyurea. However, ropeginterferon alfa-2b was better with longer-term use.
¦bPROUD-PV¸g¹L1¦~ªºÀøµ{«á¡A¬ù¦³21¢Hªº±µ¨ü¹LÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101ªvÀøªº¯f±w©M28¢Hªº±µ¨ü¹L¼Ð·ÇÀøµ{ªº¯f±w¹F¨ì¤F§¹¥þ¦å²G¾Ç¤ÏÀ³¥BµÊŦ¥¿±`ªº¥D­nÀø®Ä«ü¼Ð¡C§@ªÌ±o¨ìªºµ²½×¬O¡AÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101²Ä¤@¦~©MHU§e²{«D¦H©Êµ²ªG¡CµM¦Ó¡AÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101ªø´ÁªvÀøÀø®Ä§ó¨Î¡C

¡§Ropeginterferon alfa-2b was up-titrated cautiously in PROUD-PV,¡¨ the authors wrote. The mean efficacious dose in the PROUD-¬PV study was reached after 3.7 months in the experimental group and after 2.6 months in the standard-therapy group. The median doses at 36 months were 425 £gg (IQR=250-500) per administration of ropeginterferon alfa-2b and 1,000 mg (IQR=750-1,375) per administration of hydroxyurea, which had remained stable since month 12.
§@ªÌ´£¨ì¡G¡uÃĵØÃÄ·s¤@¥N¤zÂZ¯ÀP1101¦bÁ{§É¸ÕÅçPROUD-PV¤¤ÂÔ·V½Õ°ª¾¯¶q¡C¡¨¡vP1101²Õªº¥­§¡¦³®Ä¾¯¶q¬O3.7­Ó¤ë¡A¼Ð·ÇÀøªk²Õ¤¤ªº¥­§¡¦³®Ä¾¯¶q¬°2.6­Ó¤ë¡C36­Ó¤ë®Éªº¥­§¡¾¯¶q¬°P1101²Õ425£gg¡A¦ÓHU²Õ¬°1,000 mg¡A³o¾¯¶q±q²Ä12­Ó¤ë¤§«á¤@ª½«O«ùí©w¡C

In CONTINUATION-PV trial, a significantly higher proportion of patients treated with ropeginterferon alfa-2b achieved complete hematologic response with improved disease burden at 36 months compared with patients treated with hydroxyurea (53% vs. 38%, respectively; rate ratio = 1.42; 95% CI 1.01-2.00; p=0.044). However, there was no significant difference between the treatment groups in terms of patients who achieved the composite primary endpoint at 12 months.
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The investigators observed that the proportion of patients with a response in the ropeginterferon alfa¬2b arm of the extension trial gradually increased up to 24 months and remained high at 36 months. In contrast, the proportion of responders in the hydroxyurea group was highest at 12 months but subsequently decreased. See the TABLE for a detailed report of the types of responses observed in the CONTINUATION-PV trial.
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Responses also appeared to be more durable in the ropeginterferon alfa-2b group: A significantly greater proportion of these patients maintained complete hematologic response (39% vs. 15%, respectively; p=0.0011) and complete response with improved disease burden (30% vs. 15%; p=0.025) over 36 months.
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When looking at molecular responses, the researchers noted that, from baseline to 12 months, the reductions in mean JAK2 V617F allele burden were not significantly different between the ropeginterferon alfa¬2b group (41.9% to 30.7%, respectively) and the hydroxyurea group (42.8% to 25.9%, respectively). However, at 24 months, these values were significantly lower in patients treated with ropeginterferon alfa¬2b versus hydroxyurea (20.9% vs. 32.1%, respectively; p<0.0001). Similar findings were observed at month 36 (19.7% for ropeginterferon alfa¬2b vs. 39.3% for hydroxyurea, respectively; p<0.0001). Post hoc analysis revealed that a lower JAK2 V617F allele burden correlated with complete hematologic response at 12, 24, and 36 months.
¬ã¨s¤H­û¦bÆ[¹î¤À¤l¤ÏÀ³®Éª`·N¨ì¡AP1101²Õ©MHU²Õ¦b«e12­Ó¤ëªvÀø´Á¶¡¡A¥­§¡JAK2 V617Fµ¥¦ì°ò¦]­t¾á´î¤Ö¨ÃµL¨S¦³ÅãµÛ®t²§¡C¦ý¦b24­Ó¤ëªºªvÀø®É¶¡¡AP1101²Õ¯f±w¨ä¼Æ­ÈÅãµÛ§C©óHU²Õ¡]¤À§O¬°20.9%©M32.1%¡^¡C¦b²Ä36­Ó¤ëªºÀøµ{¤]Æ[¹î¨ì¤FÃþ¦üªºµo²{¡]P1101²Õ¬°19.7¢H¡A¦ÓHU²Õ¬°39.3 %¡^¡C¨Æ«á¤ÀªRÅã¥Ü¡A¸û§CªºJAK2V617Fµ¥¦ì°ò¦]­t¾á©M12­Ó¤ë¡B24­Ó¤ë©M36­Ó¤ë®Éªº§¹¥þ¦å²G¾Ç¤ÏÀ³¬ÛÃö¡C

In the ropeginterferon alfa-2b group, the most frequently reported grade 3 and grade 4 treatment-related adverse events (AEs) included increased gamma-glutamyltransferase (6%) and increased alanine aminotransferase (3%). In patients treated with hydroxyurea, however, the most frequently reported grade 3 and grade 4 AEs were leukopenia (5%) and thrombocytopenia (4%). Overall, the investigators found that the proportion of grade ≥3 treatment-related AEs were similar in both treatment groups, at approximately 2% in the ropeginterferon alfa-2b group and 4% in the hydroxyurea group.
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Four deaths were recorded; only one death (in the hydroxyurea group, due to acute leukemia) was considered treatment related.
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While these findings appear to corroborate the disease-modifying potential of interferon alfa¡Vbased therapy that has been demonstrated in previous trials, the authors noted several potential limitations, including the low number of patients with baseline splenomegaly, the low number of patients who consented to bone marrow assessment for the evaluation of hematologic and clinical efficacy outcomes, the potential of confounding by some patients¡¦ prior use of hydroxyurea for up to 3 years, and the possibility of selection bias in the extension study.
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Eleanor Fish shares early data (under review) on treating COVID-19 patients with interferon-alpha, following previous work showing that treatment with interferon-alpha was beneficial in patients with SARS. Eleanor is a Professor in the Department of Immunology at the University of Toronto.

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Can antivirals that target the host and not the virus improve outcomes for COVID-19 patients? Professor Eleanor Fish from the University of Toronto showed that treatment with interferon-alpha was beneficial in patients with SARS, and now shares early data on COVID-19. The webinar is moderated by Juan-Carlos Zuniga-Pflücker, the Chair of the Department of Immunology at the University of Toronto.

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In summary, the patient population investigated here was older than in published large multicenter trials. Age was the main factor accounting for the majority of patients being categorized as ¡¦high risk¡¦. Although the majority of patients (>60%) presented as ¡¦high risk¡¦ according to international guidelines, 69.4% of patients received phlebotomy as primary therapeutic approach, in part at high frequency (>25% with more than 7 phlebotomies per year). The low number of primary cytoreductive treatment and occurrence of symptomatic iron deficiency in 9.3% and of intolerance in 5.3% of patients indicates the need to reconsider indication and limitations of phlebotomy.

We conclude that phlebotomy as a prophylactic measure of risk reduction should result in mild iron-deficient erythropoiesis and hematocrit control without inducing a severe iron-deficiency syndrome as indicated by increased levels of soluble transferrin-receptor or Zn-protoporphyrin. Pharmacologic cytoreduction is necessary for high risk patients older than 60 years or with previous thromboembolic complications. For patients, who require permanent phlebotomies at high frequency for sufficient hematocrit control (<45%), pharmacologic intervention should be discussed even in the low-risk situation to balance the looming risk of iron-deficiency symptoms with potential side effects of pharmacologic compounds

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PharmaEssentia said it expects to gain approval this month.
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Fri, Apr 17, 2020 page12
PharmaEssentia seeks US FDA nod for tests
By Kao Shih-ching / Staff reporter


PharmaEssentia Corp (ÃĵØÂåÃÄ) plans to apply with the US Food and Drug Administration (FDA) to run clinical tests of its new drug Besremi for COVID-19, the firm said yesterday.

The interferon drug, which modulates immune response by interning with viral proliferation, was designed to treat polycythemia vera, a rare blood disease, and has been marketed in Europe since last year, PharmaEssentia said.

However, given that there is no specific treatment for COVID-19 and some studies have found that alpha-type interferons combined with other antiviral drugs worked against Middle East respiratory syndrome in animal tests, the firm aims to test whether its drug can treat COVID-19, PharmaEssentia chief executive officer Lin Ko-chung (ªL°êÄÁ) told a news conference in Taipei.

Moreover, studies have shown that alpha-type interferons could reduce the possibility of infection of the novel coronavirus, Lin said.

The company has prepared a plan to use Besremi to treat people infected with COVID-19, including details of target patients, dosage and optimal timing of injection to apply for the FDA¡¦s Coronavirus Treatment Acceleration Program, he said.

The company declined to reveal when it would submit its applications, only saying that it would discuss its plan with the agency first.

As the drug would normalize the immune response, it is expected to work best on mild cases and help prevent severe pneumonia, the firm said.

Immune response has been a key issue in combating the pandemic, with some studies saying that patients had severe symptoms as a result of a ¡§cytokine storm,¡¨ an overreaction of the body¡¦s immune system.

However, the company¡¦s drug would not have such concerns, as it normalizes immune response, Lin said.

PharmaEssentia¡¦s marketing partner in the EU has told the firm to prepare more Besremi for people in the bloc with myeloproliferative neoplasm, as the UK¡¦s National Health Service has warned that people with blood diseases who take ruxolitinib might develop weakened immunity, he said.

PharmaEssentia said it expects to gain approval this month.

The company in July last year applied to local regulators to market Besremi as treatment for polycythemia vera.

It submitted an application last month with the US regulator hoping to gain marketing approval for the drug as a polycythemia vera treatment by the end of this year.

PharmaEssentia posted a net loss of NT$842 million (US$27.95 million) for last year due to high research and development costs, an improvement from a net loss of NT$1.03 billion in 2018.


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