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Teva/Lonza: Rituxan biosimilar doable but not trivial; Parexel is CRO partner -sources
2010-08-13 Pharmawire
Intelligence Details
-- EMA expected to adopt stringent policies in reviewing biosimilar applications
-- Main manufacturing challenge is allowing small differences between the rituximab MAb biosimilar and the reference product without impacting safety and efficacy
-- Difficulties expected in establishing clinical safety and efficacy data in anti-tumoural settings
Teva Pharmaceutical (NASDAQ: TEVA) and Lonza (VTX:LONN) are currently working with contract research organization Parexel International (NASDAQ: PRXL) on the manufacture of a biosimilar version of Rituxan named TL011, a source close to the matter confirmed. Its progress has not been disclosed, the source said.
Experts interviewed noted that the creation of the first biosimilar monoclonal antibody (MAb) of Rituxan (rituximab) is a complicated manufacturing process, and faces a rigorous approval pathway. If approved, it will be the first MAb biosimilar in the EU.
Biogen-Idec (NASDAQ:BIIB) and Genentech are partners on Rituxan. Roche (PINK:RHHBY) is marketing the drug under the tradename Mabthera in the EU. Rituxan and Mabthera are indicated for chronic lymphocytic leukemia and non-hodgkin’s lymphoma. Rituxan also has another indication for rheumatoid arthriitis (RA) in combination with methotrexate.
Six investigational sites in Hungary are currently conducting trials evaluating TL011, with only one site that has started recruiting, according to Clinicaltrials.gov. The study evalutes TL011 in severe, active RA patients against active comparator Mabthera. The estimated enrollment is 60 patients, and started in February. The estimated primary completion date is April 2011.
TL011 is intended as a replacement biologic for RA patients who are prescribed Rituxan. It is unclear whether or when Teva and Lonza plan to apply for approval as a biosimilar across all of Rituxan's currently marketed indications.
Teva and Lonza did not respond to requests for comments by press time.
The European Medicines Agency (EMA) is currently developing guidelines on the development of biosimilar MAbs with no exact timeline given for its draft issue, noted Dr Peter Gaskin, principal regulatory consultant at Aptuit Consulting. The guideline should "hopefully" ensure the "right balance of determining clinically relevant comparability whilst allowing small differences between innovator and biosimilar products which do not impact on safety or efficacy," he said. Still, he noted that the EMA will place particular regulatory scrutiny on MAb biosimilars due to their complex structure.
The EMA said in an e-mail that establishing similar clinical efficacy and safety of a biosimilar in an anti-tumoural setting may be more of a challenge than in a non-tumoural setting. "Cancer is a critical clinical condition where lower efficacy would be of particular concern," it said. Usual time-related endpoints to establish patients’ benefit (such as overall survival or progression-free survival) are confounded by various factors such as tumour burden, previous lines of treatment and underlying conditions to name a few. Therefore these endpoints may not be suitable for a biosimilarity exercise to establish therapeutic equivalence with its reference product, it added.
Additionally, the EMA said for some MAbs, the clinical applications in cancer can be considerably divergent, for example, adjuvant treatment as opposed to last-line therapy in a metastatic setting. In the case of rituximab, the scientific justification for extrapolation of data between the two (or more) applications is particularly challenging. The basis for such extrapolation relies on an extensive and quality non-clinical database, including potency assays and in vitro assays that cover the functionality of the molecule. The burden of proof for extrapolation of clinical efficacy between different indications lies on the applicant (Teva/Lonza) and acceptability for such extrapolation has to be considered on a case-by-case basis, it said.
Gaskin agreed with the EMA that the question is whether clinical safety and efficacy information can be extrapolated from one autoimmune condition to another or whether that data can be relevant for an anti-cancer indication. He also said that clinical considerations should also include the heterogeneity of the patient population and the feasibility of clinical trial design such as the number of patients that would be required. Finally, a well-planned post-marketing safety follow-up will likely be required to ensure that the product can remain on the market after approval, he said.
No MAb biosimilar has been authorised yet and given the complexity of a MAb, it is too early for the European Medicines Agency to draw a definite conclusion on whether the manufacturing of one would be a success, according to an e-mail sent by the EMA. It said the complex mode of action of rituximab is "definitely possible" to recreate but there may be issues in that potency assays may not able to discriminate differences from the reference product.
Gaskin agreed, adding that well-designed comparative studies will be critical to overcome the potency assay concerns. He said all European biosimilars approved to date are smaller and are less complex molecules. "Characterising an MAb is significantly more complex with a greater likelihood of small differences between innovator and biosimilar products," he said.
An EU policy expert and scientist said if every moiety in rituximab was determined safe and enough moieties assured efficacy, then "goal posts" could be developed for a biosimilar to fit into. She said this is "doable" but it is not a trivial exercise, so the burden will be on Teva and Lonza to illustrate this well in their submission data.
There are still no clear markers to identify for which patients the MAbs will work, noted Kathryn Mertes-Egeland, founder of the consulting firm BRANDominance. She noted that it has been shown in studies that among patients who take the top-selling RA drugs -- Rituxan, Pfizer (NYSE:PFE) and Amgen’s (NASDAQ:AMGN) Enbrel (etanercept) and Abbott’s (NYSE:ABT) Humira (adalimumab) -- one-third do not experience any benefit. Likewise, there is no way to determine upfront how well a biosimilar will work for patients. She said even if a biosimilar demonstrated bioequivalence, it is difficult to determine performance compared to branded therapy until tested in patient samples.
Clinical trials for a biosimilar rituximab would not be unheard of considering its complexity, experts noted. EMA policy dictates that it already can require such trials if there are "greater" differences in quality between the reference product and the biosimilar. Mertes-Egeland noted that she expects the EMA to adopt increasingly stringent policies for biosimilars, including full Phase III clinical trials to ensure similar performance between the reference product and biosimilar and post-approval safety monitoring, in light of countries such as India and China doing the same. Clinical trials for biosmilars seem likely as well in that there are inherent variations of biologics, she added.
The scientist noted that in having spoken to lead EU regulators, "the goal in any regulatory decision on a biosimilar is de facto interchangeability and full comparability standards are expected."
Teva has a market cap of USD 46.76bn.
by Surani Fernando in London and Jennifer C. Smith in Washington, DC
Endocyte narrows CRO search for Phase III ovarian cancer trial; financing still being secured, CFO says
2010-07-01 Pharmawire
Intelligence Details
Endocyte, the privately held West Lafayette, Indiana-based firm, will retain a clinical research organisation (CRO) to run its pivotal Phase III trial investigating EC145 in platinum resistant ovarian cancer by the end of the summer, CFO Michael Sherman said. The firm has narrowed the selection down from four or five firms and is currently finalising funding for the trial, he added.
Sherman said that the company will collaborate with a CRO that has experience in running Phase III ovarian cancer trials. He declined to comment on which countries will be involved in the trial, but said that the firm is currently in discussions with both localised and global CROs. The firm previously worked with the CRO ACM Global for its Phase II trials, a person familiar with the matter noted. ACM declined to comment.
In October last year Endocyte secured USD 23m in an extension to its series C financing round. Endocyte is still in the process of securing funding for the Phase III trial, Sherman said, but declined to comment on the type of investors the company is in engaged with. Yet the person familiar with the company said it was their understanding that Endocyte had secured financing and added that the trial will be venture capital backed.
Sherman said Endocyte plans to initiate the Phase III trial towards the end of the year. Yet the person familiar claimed to have heard from the company that the trial will be initiated in the next two months. A second person familiar also relayed this timeline. The trial is currently being finalised, the first person added. Sherman said that the trial is still in the planning stage and insisted that the firm will not be ready for this timeline.
Although details are yet to be finalised, Sherman said the Phase III trial will include around 500 patients, adding that similar studies usually cost around USD 45,000 to USD 55,000 per patient. The first person said that the Phase III design will be very similar to the ongoing randomised Phase IIb trial investigating EC145 in combination with doxil.
When asked whether Endocyte is currently seeking a partner for EC145, Sherman said the firm is keeping its options open, adding that it could potentially take the drug to market itself. He declined to comment further. The two persons familiar said that they are not aware of a licensing deal at the moment. The first person said it is possible the firm could take the drug to market itself.
On 19 October 2009, this news service cited Sherman as saying: “Endocyte will monitor the market for signs of recovery and consider a public offering but has no immediate plans.” When asked whether the company is currently considering a public offering, Sherman said that he is not able to comment on financing activity or partnering strategies publicly.
One clinical expert commented that the interim Phase IIb trial data reported at the American Society of Clinical Oncology 2010 is promising and suggests that EC145 is very active. The data showed a progression free survival advantage of almost double that of the control arm.
A second clinical expert noted that the secondary endpoint, overall survival (OS), did not show significance but indicated a trend. The survival curve for the OS reported a p-value of 0.6 and a hazard ratio of 0.42 in a one-sided test, Sherman said.
The Phase IIb randomised trial could potentially show a signal on OS in the final analysis, the second expert speculated, adding that a signal on OS could potentially lead to early approval. Yet a person familiar with the regulatory and registration process for oncology drugs said that regulatory agencies will require more safety data than the company currently holds. When questioned on the issue, Sherman said: “It would be inappropriate to speculate on regulatory strategy.”
The second expert noted that so far the safety profile of the drug is encouraging. The first expert noted that it is important to regard early Phase II results with caution as statistics show that only 8% of positive Phase II trials in the space result in a positive Phase III trial. Although these statistics are based on non-randomised trials, it is still necessary to note them, the same expert added.
At the time of the interim data, the trial had enrolled around 90 patients and 46 events had occurred. The study is now fully enrolled with around 150 patients and the total number of events needed to stop the trial is 95, Sherman said.
According to Endocyte’s website, EC145 targets a chemotherapy drug to folate receptors overexpressed on cancer cells. More than 80% of ovarian cancer patients show an up-regulation of folate receptors, according to the second person. Other cancers that are believed to have a significant up-regulation of the folate receptors are small cell lung cancer and pancreatic cancer, according to the first person familiar. The person added that pancreatic cancer is likely to be the next indication the company will target. Other potential targets could include colorectal cancer and breast cancer, Sherman said.
by Abigail Moss in London
Kissei working with CRO Richmond Pharmacology for Phase I endometriosis trial; recruitment delays occurring
2010-07-01 Pharmawire
Intelligence Details
Kissei Pharmaceutical (TYO:4547) has hired UK-based contract research organization (CRO) Richmond Pharmacology to undertake a series of Phase I first-in-man studies of KLH-2109 although recruitment delays are occurring, it is understood.
KLH-2109 is being developed for endometriosis and uterine fibroids. The trial protocol is challenging in terms of recruitment as it requires that women are at a very specific time in their menstrual cycle and are on contraception for three months after the trial.
Kissei and Richmond Pharmacology did not respond to request for comment prior to publishing.
According to public information, the study is divided up into two parts, consisting of several groups. Part A involves a single ascending dose of KLH-2109 in healthy Caucasian and Japanese pre- and post-menopausal females, and Part B involves multiple ascending doses in pre-menopausal females.
Part A is currently underway, for which volunteers are required to attend a screening visit up to 28 days before the start of the study and stay at the clinical site for six days and five nights. Group 5 admissions were scheduled for 20 June, Group 7 admissions were scheduled for 22 June and Group 6 admissions were scheduled for 27 June.
Participants will receive remuneration of GBP 680 (USD 1,025) for Part A and other last minute incentives are being offered by Richmond Pharmacology to attract volunteers, such as a chance to win a holiday to Spain or several hundred pounds worth of holiday travel vouchers, it is understood.
Yet it is also understood that Richmond Pharmacology is still attempting to recruit five patients for the second (Group 7) admission. The planned 22 June admission date has already passed and the CRO had to push back the date as it was still short five patients. The latest date for Group 7 admissions was Wednesday, 30 June, yet the day prior, the firm was still seeking five volunteers.
According to the planned timeline, Group 6 of Part A is also already behind schedule and Part B - consisting of Groups 1, 2 and 3 - is due to start admissions soon (11, 20 and 30 July, respectively) yet recruitment for this part is more complicated than for Part A.
For Part B, volunteers are required to attend a first screening visit between 27-60 days prior to the start of the study and a second screening visit between 3-30 days prior to the start. Volunteers are then required to stay at the clinical unit for 13 days and 12 nights. Participants will receive remuneration of GBP 1,560 (USD 2,340).
by Kirsty Barnes in London