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, Ahmed Kotb, MD, discussed findings from a trial investigating navitoclax for the treatment of myelofibrosis. In safety findings from the trial, thrombocytopenia was the most common adverse effect, which was managed through dose reduction.

Q: What were the most common adverse effects and how severe were these?

I think it's important to look at the holistic data set. I think it's important to see the efficacy as well as the safety together. And let's look at the cohort 3. This is the cohort where navitoclax was added to ruxolitinib in the JAK-naive patient population. The primary endpoint, as I mentioned, was SVR35. And here, what we saw was about 63% of the patients achieved this endpoint at the 6-month landmark, as I mentioned, 24 weeks. This is quite unprecedented in this disease area.

What we also saw was that the longer you treated patients, more patients responded. So, we saw best overall response in about 78%. Again, this is very encouraging for us. We have a phase 3 trial that's ongoing, that is looking exactly at that, adding navitoclax-ruxolitinib versus ruxolitinib alone, so we're quite excited to see the outcomes of that study, because we believe this may be practice changing. At the same time, the other endpoints, like total symptom score reduction was about 40%. Again, very encouraging. We also saw that about a third of the patients showed a reduction in the bone marrow fibrosis. And what was very interesting was that irrespective of the amount of fibrosis the patient had at baseline, whether it was a lot of fibrosis or intermediate or a little amount of fibrosis, they had the chance to decrease this bone marrow fibrosis. So that was about 35%. So, that was also quite interesting and gives us the confidence that this agent may be having a disease modification potential.

From a side effect perspective, from an adverse event perspective, the most common adverse event was thrombocytopenia, it occurred in about 80% of the patients. It's an on-target side effect because BCL-XL, which is the target of navitoclax, is highly expressed on thrombocytopenia, thrombocytes, or platelets. So, we expected that it's a predictable and manageable adverse event. We didn't see any clinically meaningful bleeds happen in the study.

Q: How can these adverse effects be managed?

So, so far, we have not really seen that this adverse event has impacted the outcomes of therapy. It's kind of included within the outcomes that I've just mentioned. The way we manage it within the protocol is we do reduce the dose and when it gets to a certain level, we sometimes dose interrupt. We still keep baseline therapy, which is ruxolitinib. It's also important to know that thrombocytopenia is a side effect of both the agents, navitoclax and ruxolitinib, so there is an algorithm of how this is being managed.

Q: Is there anything you would like to add?

No, I think this is very exciting. I think that this is a new mechanism of action in a disease area that has not seen much advances over the last decades. I think we're quite hopeful that this molecule will add options to patients and to physicians. As I mentioned, we have a phase 3 trial, the TRANSFORM-1, which is running in the frontline setting. We also have a phase 3 trial that is running in the relapsed/refractory setting. We're hoping to see data from these studies by end of this year, early next year, and we will use this data to register navitoclax and hopefully bring it to patients in need. This also shows the investment that AbbVie is doing in oncology and the way we're trying to drive innovations across multiple blood cancers. We've obviously done a lot in CLL with venetoclax and IMBRUVICA. We're doing a lot also in AML with venetoclax, and we're expanding our portfolio to touch other blood cancers like lymphomas with epcoritamab, we have exciting data coming at EHA, and also you're going to see data here at ASCO from our solid tumor program. So, it really speaks to the breadth of our oncology portfolio and how we're evolving that.

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Thrombocytopenia was the most common adverse effect, which was managed through dose reduction.

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® Oncology Clinical Role section is a comprehensive resource for clinical news and expert insights on issues pertaining to oncology pharmacists.

Manage Adverse Effects Associated With Navitoclax in Patients With Myelofibrosis

 interviewed Zahra Mahmoudjafari, PharmD, BCOP, DPLA; Alison Gulbis, PharmD, BCOP; and Kamakshi Rao, PharmD, BCOP, FASHP, on a 2022 ATOPP Summit session they will be co-presenting addressing research they conducted assessing the underlying causes of the hematology-oncology pharmacist great migration.

 Where are hematology-oncology pharmacists migrating to for the most part?

 Well, that is a great question. That's not something we could pull out from the survey, but speaking from what we know of people going, I'd say a lot of them went into pharmaceutical industry, especially with the increase in CAR-T products and other opportunities out there that were opening up for medical science liaison positions, etc. I think a lot of people have gone to that.

But in addition to that, there have been a lot of other nontraditional pharmacy roles that have opened up that people with clinical expertise really are being recruited for. That includes things like working for insurance companies, as a clinical pharmacist to help with decisions they may have to make with formularies or other access issues patients might have. There's health information technology, tons of people are looking for clinical pharmacists to help with the sector of the electronic health record [(EHR)] and how to build orderable, especially for chemotherapy, etc, and best practices and data mining, and looking at how do you pull data and extract it out of the EHR and bring it back to take care of the patient better.

So those are some nontraditional roles that I think are becoming more appealing to people also, because they're remote positions, for the most part. So I think those will be trends that continue. You may see a more equal shift across different types of positions that might be out there, not just industry.

 I would definitely echo that what we saw in our research, we have to absolutely acknowledge that our colleagues are well-trained and well-positioned to take on these roles, and that the title of clinical pharmacist is evolving.

There's also, to add to what Alison said, opportunities in continuing education, and some of our colleagues have moved onto support those types of roles. So there's no shortage of opportunities, and I have to acknowledge, that doesn't necessarily mean that clinical pharmacists are going to necessarily be in direct patient care roles like we were when we were training.

 Has there been any research conducted looking to assess this migration from the field?

 So there's a lot of research on burnout in health care professionals, and pharmacists get lumped into that in a lot of those surveys that have been done within the past 5 to 10 years. I think that what hasn't been addressed directly in terms of a study is how do you mitigate these migration issues, how do you keep and retain your employees, and how do you come up with ways to show that you appreciate them that you recognize their hard work their doing and that you're willing to give them time to do professional development activities.

There's commentary on that in some publications, but how do you make that go into play and how do you measure if that works to keep employees. That hasn't been research that's been done that I've been able to find.

 Yeah, I would say that was that was the motivation here is that we've had those anecdotal stories, we've heard the commentary, and we've read the opinion papers, but what we really thought was there's power that could be had if we could aggregate that data and start to show that it's not an institutional issue, it's not a regional issue; it's a nationwide professional issue. So that was really the goal when we started was to make sure that every oncology pharmacist in the country had a voice that we could aggregate together to show some power, and I think that's exactly what we saw in the study.

In that survey that we sent out we asked some directed questions around job satisfaction, around how that correlated with a desire to consider alternate careers or changing careers, but then we actually left an open commentary section, and that was the part that I think when we got results, I sent Zarah and Alison an email saying we have a couple of hours or days of reading ahead of us, because people just bared their souls, and it was so powerful to read those words.

As we started to really affinitize that data, it was so clear that it was common themes coming across consistently, so as 3 of us really sat and all 3 of us have read all the comments, we feel really confident that this is a really powerful way of looking at this data as a whole. So ours is just one piece that I would say warrants repetition throughout the pharmacy profession.

Is this migration occurring across the field among hematology-oncology professionals beyond pharmacy, or is it primarily occurring among pharmacists?

 I'd say yes, it is occurring across health care, not just hematology/oncology. I think even beyond health care, when you read articles about the “Great Resignation,” they don't focus just on health care professionals.

It's hard to pinpoint if, like we said earlier, is this because of the pandemic and all the things that occurred with it. Clearly, something has happening for people to notice it and talk about it, whether it be through a commentary in the 

 or other places where they're talking about this, but yeah, I think it's an issue across the board.

It might be that maybe we need to revisit all human professionals or all health care professionals, and are they doing what they should do at the top of their license? Do we need to make sure we're not giving administrative tasks to people who shouldn't be getting certain administrative tasks? Do we need to make sure we're giving protected time to all these people to develop professionally, because professional development is vital in health care in general, to make sure that you're on top of things, and you're in the know, with the new research and that you're networking with people. I think that was a big thing COVID-19 took away from us to networking with people. That's made an impact on how people rethink what they're doing across health care, and is this what they want doing and be in?

What is your outlook on the future for hematology-oncology pharmacy?

 That's a big question because there's a lot of weight behind that answer. But, quite honestly, I've been a hematology/oncology pharmacist for over 20 years now, and I remain optimistic about the impact and the value that hematology/oncology pharmacy professionals and pharmacists can have.

It is so clear the value that we have in helping optimize patient care and collaborating with our other health care providers and professionals to do strong research to teach and to advance care. Those opportunities all exist, and they will continue to grow over time. As all 3 of us are involved heavily in education as well, it's great to see the amount of interest there is in joining this profession and being part of that.

I would say there's a challenge to the profession as well. I think it is going to require local institutions and our profession as a whole to really embark on some very serious cultural change: It's about changing our value proposition and it's about trying to blend the business-minded pharmacy with the idea that we are a people-oriented profession, not just for our patients, but for the people that actually do the work. I think that the evolving focus and the evolving attention around building inclusive work environments is absolutely necessary to be leaned into.

So I think there is a challenge ahead for those that are trying to leave this profession to make it one that continues to be someplace that people choose to join, and maybe more importantly, a place that people choose to stay. I think a lot of people see clinical practice as that first entry point out of postgraduate training, our challenge is going to be how do we get them to see it as a place where they can continue to grow and evolve for a long swath of their career.

 Well, I feel like we've laid a lot out the issues and the problems, but I think there's also strategies to mitigate and make things better. So I don't think we want to leave this all doom and gloom. I think there's great promise for us.

I think from a mitigation and how do we move this in the right direction standpoint, I think it's a couple of things, and I invite my co-authors here to chime in. I think, on one hand, is just recognition that the landscape of opportunity has changed and supporting our people so that every individual has the opportunity to realize their best potential, whether that be within the patient care environment or outside is part of our job to move people into the roles that they best deserve.

I think a lot of times people migrating into roles outside of direct patient care, we've all heard the terms people say, 

‘Oh, they're moving to the dark side of admin or the dark side of industry.’

 Realistically, there are just so many sides, so I am more interested in people finding where they belong versus feeling like they are running from jobs that aren't satisfying and that don't have the right reward ratio.

I think individuals have a responsibility to communicate with their managers and managers have a responsibility to open, vulnerable, and thoughtful conversations with employees so you can understand what each individual is looking for. If we can really engage in getting to know the people who are helping us deliver care, then there's nothing that we can't do and there's nothing that we can't get past.

 Well, I agree, I would say we have an opportunity now. We understand the issue, we understand what it is our team members are asking for, so I think, as practice managers, we have to continue to advocate for, like Kamakshi said, our value, not only within our organizations but within ourselves, but also outside of our departments, with our providers, with our nursing colleagues, etc so they can give support to our pharmacists that are with us and are working day in and day out, trying to make their lives a little bit easier, giving them that time that they need to do the teaching, do the research, supporting them in whatever support means to them. And then recognizing that patient care is extra ordinary, it should not be ordinary, and making sure that they feel valued as well.

We also have an opportunity, as Kamakshi said, to figure out this value metric and apply it to clinical pharmacy in a way that's meaningful and not just institutionally specific, as that's something we definitely have yet to define from a clinical pharmacy standpoint. So I see opportunity to talk about this, and we've looked up the data and now we need to work on the next steps. So we're really looking forward to the discussion in San Diego and presenting the research. It's near and dear to us so it’s a exciting to present it because we've been sitting on it for a little bit and we're really excited to show it off and to really start the discussion with everyone.

Zahra Mahmoudjafari, PharmD, BCOP, DPLA; Alison Gulbis, PharmD, BCOP; and Kamakshi Rao, PharmD, BCOP, FASHP, discuss research conducted looking to assess the hematology-oncology pharmacist “great migration” from the field.

Hematology

® Hematology Resource Center is a comprehensive resource for clinical news and expert insights on the treatment of blood disorders, include blood and bone marrow cancers, anemia, hemophilia, blood-clotting disorders, and leukemia.

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Expert: The Great Migration of Hematology, Oncology Pharmacists Brings a Call to Action for the Field

 (Absorica) is an FDA-approved oral dosage form of isotretinoin indicated to treat severe recalcitrant nodular acne. The FDA initially approved this retinoid in 1982 and pharmaceutical firms have marketed it in various dosage forms over the past 40 years.

Although very effective for nodular acne, pharmacists may be aware of oral isotretinoin’s disadvantages. Because isotretinoin is lipophilic, pharmacists have historically needed to counsel patients to take isotretinoin with a full, potentially higher fat meal. First approved in 2012, patients can take this specific lipid-encapsulated formulation without regard to meals.

A double-blind, randomized, parallel group trial confirmed the efficacy of this isotretinoin formulation. Researchers randomized 925 patients 12 years of age and older with severe recalcitrant nodular acne to either lipid-encapsulated isotretinoin or another oral isotretinoin capsule.

All study participants received 0.5 mg/kg/day in 2 divided doses for 4 weeks, followed by 1 mg/kg/day in 2 divided doses for 16 weeks. The researchers screened participants for total nodular lesion count every 4 weeks during the trial.

At week 20, more than 70% of isotretinoin in both groups (70% in the lipid-encapsulated isotretinoin group vs 75% in the comparator group) experienced a 90% reduction in total nodular lesion count from their baseline measurements.

The exact mechanism regarding the treatment of nodular acne is not fully understood. Like other retinoids, isotretinoin generally affects epithelial cells. It exerts dose-dependent inhibition of sebaceous gland function, thereby reducing sebum secretion, which is associated with improvement in nodular acne.

 Isotretinoin may also have additional beneficial effects, inhibiting keratinization and inflammation.

This formulation of isotretinoin is only approved for non-pregnant patients 12 years of age or older. Patients must also have failed to respond to other therapies, including systemic antimicrobials.

Isotretinoin is initially dosed at 0.5 to 1 mg/kg/day in 2 divided doses for most patients. Some patients with severe nodular acne causing scarring or manifesting on the trunk may require treatment with 2 mg/kg/day in 2 divided doses (

This particular form of isotretinoin can be given without regard to meals. Pharmacists should remember to dose based on actual body weight; however, the efficacy study cohort only included patients weighing up to 110 kg.

After a treatment duration of 15 to 20 weeks, prescribers can discontinue lipid-encapsulated isotretinoin if the total nodule count is reduced by at least 70%. A second course of therapy may be initiated but should not be started within 2 months of the previous course.

To avoid esophageal irritation, pharmacists should counsel patients to take their dose with a full glass of liquid. Patients forgetting a dose cannot take an extra dose and should be advised to skip the missed dose.

The most common adverse events (AE) include dry skin, headache, increased creatinine kinase, upper respiratory infection, and reduced visual acuity. These AEs have been reported in 5% or more of patients treated with isotretinoin.

As previously suggested, isotretinoin therapy is associated with significant side effects and toxicities. Isotretinoin includes a boxed warning due to an extremely high risk of embryo-fetal toxicity in pregnant patients and is, therefore, contraindicated in pregnancy.

It is only available through the iPLEDGE risk evaluation and mitigation strategy (REMS) to prevent use in pregnancy. Patients, prescribers, and pharmacies must be certified and registered with the REMS program before treating any patient with isotretinoin.

Providers need to be aware of the risk of psychiatric disturbances, including suicidal ideation, associated with isotretinoin therapy. Pharmacists should counsel patients and caregivers to report changes in the patient’s mood or behavior to their prescribers.

Isotretinoin is contraindicated in patients with a previous allergic reaction to isotretinoin and vitamin A. Due to post-marketing reports of life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), providers need to monitor patients for skin reactions.

Significant increases in triglycerides (>800 mg/dL) can occur in patients taking isotretinoin, and fatal cases of hemorrhagic pancreatitis have been reported. Lipid levels should be drawn at baseline and then periodically during treatment. Providers need to counsel patients to report any potential symptoms of pancreatitis at any time while receiving isotretinoin.

Pharmacists should counsel patients and caregivers to stop isotretinoin and contact the patient’s prescriber if any of these discussed symptoms occur. Due to an increased risk of intracranial hemorrhage with isotretinoin, concurrent tetracycline use should be avoided.

Pharmacists should also be aware of corticosteroids, phenytoin, and isotretinoin interactions. These agents can all potentially cause detrimental effects on musculoskeletal health and prescribers need to discuss concurrent therapy with patients.

Patients need to also avoid progesterone preparation, or “minipills,” as contraception due to inadequate contraceptive potential when given with isotretinoin. Pharmacists need to caution patients against the use of St. John’s Wort because of reports of pregnancies when combined with hormonal contraceptives.

Serious fetal harm, including congenital malformations and spontaneous abortion, can occur after isotretinoin use in pregnancy. Any patient capable of becoming pregnant must follow all iPLEDGE requirements, including 2 confirmed negative CLIA-certified laboratory conducted pregnancy tests. Pregnancy tests must be repeated each month, at the end of isotretinoin treatment, and one month after isotretinoin therapy discontinuation.

Patients who can become pregnant need to use 2 simultaneous forms of contraception for 1 month preceding, during, and 1 month after receiving isotretinoin. If unprotected sex occurs during this time, patients should stop taking isotretinoin and contact their prescriber for further instructions.

If a patient becomes pregnant, isotretinoin must be immediately discontinued. Further follow-up should occur with an OBGYN practitioner. Any fetal exposure to isotretinoin should be reported to FDA MedWatch and the iPLEDGE registry.

Due to potential infant risk, patients should be advised that breastfeeding is not recommended during treatment with isotretinoin and for at least 8 days after the last dose of isotretinoin.

Edmond M Nunes, PharmD, RPh, BCSCP is the pharmacy clinical coordinator at Sturdy Memorial Hospital in Attleboro, MA.

1. Absorica/Absorica LD is prescribing information. November 2019. Accessed May 14, 2022. 

https://www.absoricald.com/pdf/absoricald-prescribing-information.pdf

. 2021;20(5):s3-4. doi: 10.36849/JDD.s0721.

3. Jones M, Armstrong AW, Baldwin H, et al. Advances in oral isotretinoin therapy. 

. 2021;20(5):s5-s11. doi: 10.36849/JDD.s072A.

4. Zaenglein AI, Pathy AI, Sclosser BJ, et al. Guidelines of care for the management of acne vulgaris. 

5. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. 

. 2021;379:361-72. doi: 10.1016/s0140-6736(11)60321-8.

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Isotretinoin exerts dose-dependent inhibition of sebaceous gland function, thereby reducing sebum secretion, which is associated with improvement in nodular acne.

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Clinical Overview: Isotretinoin (Absorica) for Severe Recalcitrant Nodular Acne

 interviewed Ken Thorpe, PhD, professor of public health at Emory University and chairman of Partnership to Fight Chronic Disease, on legislation that the US House of Representatives passed to put greater restrictions on the FDA’s accelerated approval pathway.

. Joining me is Ken Thorpe, a professor of public health at Emory University and a chairman of the Partnership to Fight Chronic Disease. Ken is here to discuss legislation that the US House of Representatives just passed to put greater restrictions on the FDA’s accelerated approval pathway.

So Ken, what is this legislation and what exactly does it restrict?

 Well, it's a piece of legislation that passed the House has yet to pass through the Senate. But in essence, what it’s saying is that it gives the Secretary broad authority to require, prior to approval in the program, that a drug go through a post-approval study. So at least have that setup.

Also it does give the Secretary the flexibility to not require one, and if it's not required, they would have to publish the reason why under the FDA website, given the rationale for it. So it's really just tightening up this process of really the post-approval confirmatory studies.

 You mentioned, just as a follow up, the Secretary—is the Secretary someone within the FDA or someone appointed by legislators?

 No, it would be over at the FDA. So it would be an FDA decision in terms of how this goes. The idea is to really, as the drug is getting approved, that there'd be a methodology laid out, enrollment targets, really the structure of the post-approval study process would have to be sitting there. Then the company, the manufacturer would have to provide some indication of progress within 180 days after the accelerated approval has been okayed.

So I think there was some concern that some of these medications that went through the accelerated approval process or not, on a timely basis, really going through the more formal confirmatory studies, although, again, most of them did, so approximately 80% of the drugs that are approved through the accelerated approval process, ultimately are approved through the traditional FDA evaluation method.

 Does the passing of this legislation in the House result in any immediate action or does that not take place until the Senate makes a decision?

 Yeah, no, there's no immediate action. We're going to have to wait on the Senate to pass their version. This is on the FDA user fee program, so there's some urgency to get it passed by next fiscal year on October 1. But the versions are somewhat different though, on the non-FDA user fee components. So they're going to have to come up with a reconciliation of sorts, to get both of the bills to match up on the language with this accelerated approval process. So no immediate action now.

 Why was the FDA’s accelerated approval pathway developed in the first place, and what have been the results of its development to date?

 Well, it was approved some time ago, really in response to the HIV/AIDS epidemic. At that time, obviously, that was a disease that we really had no treatment options for and the mortality rates, obviously, were very, very high. So the FDA put into place a process that they could get medications and treatments out to HIV/AIDS patients in a much faster time period, just given the seriousness of that illness. So, it has been incredibly successful, particularly for cancer patients and patients with rare diseases.

The process started in 1992, and there's been over 270 treatments that have been approved since then. So, I think the results have been impressive. There's been a reduction in cancer mortality deaths since 1992. Those types of medications, whether they be cancer or rare disease drugs, come to market a little over 3 years faster than they otherwise would. So it's really a critically important part of treating patients that have maybe limited, if no other, treatment options.

 What are the arguments being made by the critics of the FDA is accelerated approval pathway, and is there any validity to these arguments?

 Well, the argument that I hear most frequently is that the process is expensive, and that these medications are costing, particularly Medicaid programs, a lot of money. So we've spent a lot of time looking at that issue, just to see what role accelerated approval drugs play in the Medicaid budget and in the growth of Medicaid spending.

We've gone back to 2007 looking at this, and what we have found is that the growth of accelerated approval drug spending accounts for less than one half of 1% of the growth in Medicaid spending, and in any particular year, they account for less than one half of 1% of the total Medicaid budget. So I think that this criticism and concern of the program is really unfounded, they really don't consider they'll contribute to the growth and level of Medicaid spending.

We know that Medicaid expenditures are driving up because of increased enrollment, but also because they have to provide treatment to really expensive patients, disabled patients, that are eligible for both Medicare and Medicaid. That's where most of the spending is—roughly 40% of the Medicaid budget goes to treating those types of patients. So I think if we're really serious about slowing the growth in Medicaid spending, that we really need to look at what's driving it in the first place and the accelerated approval drugs or not.

 As a follow up question, do you believe or think that the impact of vaccine hesitancy that really emerged as a key problem during the pandemic in terms of vaccine uptake that that might have some role in this decision or this legislation that just passed the House?

 I don't think so. I really do think that a lot of this is coming from unfounded financial concerns, we've seen this from a couple of states that are asking for some flexibility in terms of how much they pay for these medications.

But again, as you look at the data on this, it really is not a driving concern for Medicaid budgets. So I think that, sure, I think it makes some sense to look at the timeline of some of the confirmatory trials post approval. Hopefully, just continue to give flexibility to the FDA to say, well, we really don't need to do this, and here's the reason why. But that's really the major thrust of what the House has passed.

 What are the arguments in support of the continuation of the FDA’s accelerated approval pathway, and do you think that these arguments might be paid a bit more attention in the Senate?

 I hope so. The main benefit is that it saves time and lives, instead of waiting years for an experimental drug to show a primary clinical endpoint, like prolonging the life of a cancer patient. In a clinical trial, this process allows the use of surrogate endpoints like shrinking a tumor, which are associated with extended life, and to get those new treatments to patients faster. Like I said, something on the order of 3 to 3 and a half years faster than otherwise would happen. So I think it's an incredibly important tool for treating patients that have cancer and rare diseases, and as we've seen it has been critically important in the HIV/AIDS world.

 How could this legislation impact the future of drug approvals?

 Again, I don't know that it's going to have a huge impact. Again, as I've mentioned, it's just providing some additional structure on the timing of when the manufacturers have to do the post-approval confirmatory, more traditional studies, and it gives give some guidance in terms of when the study layout has to be outlined. You'd have to provide reports back to the FDA within 180 days post approval just on the progress of what's going on. So I don't think the process will change, it's just more this timing and structure of these confirmatory studies that that have to happen.

 Yeah, I just want to say hopefully that when it's finally done, we don't want to create any uncertainty about drugs’ likely approval; this program has been incredibly successful in getting treatments to patients.

I understand the rationale for putting some more structure on the timing of confirmatory studies, and hopefully, the flexibility the FDA would retain and not requiring them, but we just certainly wouldn't want to raise concern or doubts about a drugs’ likely approval because it really has been such an important program for large number of patients that otherwise may not have other treatment options.

Ken Thorpe, PhD, professor of public health at Emory University and chairman of Partnership to Fight Chronic Disease, discusses legislation that the US House of Representatives recently passed to put greater restrictions on the FDA’s accelerated approval pathway.

Implications of Legislation Passed in the House That Places Restrictions on FDA Accelerated Approval Pathway for Cancer, Rare Disease Drug Pipeline

Novartis announced new data from the phase 3 ASCLEPIOS 1/2 and the ALITHIOS open-label extension showing continuous treatment with ofatumumab (Kesimpta) for relapsing forms of multiple sclerosis (RMS) significantly increased the odds of achieving no evidence of disease activity (NEDA-3) compared to switching from teriflunomide. The data were presented at the European Academy of Neurology Annual Meeting held in Vienna, Austria.

“Early initiation of high-efficacy therapies for the treatment of relapsing multiple sclerosis has been shown to improve long-term outcomes versus escalating from lower efficacy therapies,” Ludwig Kappos from University Hospital Basel, said in a statement. “NEDA-3 is an important endpoint for physicians to consider when deciding to initiate high efficacy therapy, with this latest data from ALITHIOS we can clearly see the benefit of starting [ofatumumab] early versus switching to it later from teriflunomide.”

The data show that after 4 years of treatment, 78.8% of those who continuously received ofatumumab achieved NEDA-3, which was defined as having no MS relapses, no disability worsening, and no MRI activity compared to 51.8% of those who switched from teriflunomide to ofatumumab in the extension phase.

The results build on previously presented efficacy data from both studies, showing sustained differences in cumulative responses, MRI lesion activity, and the risk of disability worsening between patients continuously treated with ofatumumab versus those who were switched at a later date.

Ofatumumab is a targeted treatment that is precisely dosed to deliver B-cell therapy and provides the flexibility of self-administration for adults with RMS. The drug is designed to be delivered subcutaneously via a once-a-month injection.

Ofatumumab is currently approved for treatment of RMS in the United States, European Union, United Kingdom, Canada, China, Switzerland, Singapore, Australia, Japan, Argentina, United Arab Emirates, Albania, and India.

According to the Mayo Clinic, MS is a disabling disease of the central nervous system, including the brain and the spinal cord. The cause of MS is unknown, and it is considered an autoimmune disease in which the body’s immune system attacks its own tissues. The immune system malfunction destroys the fatty substances that coats protective nerve fibers.

Individuals with MS can experience muscle stiffness, muscle spasms, paralysis, problems with bladder, bowel, or sexual functions, mental changes, depression, and epilepsy.

New Novartis extension phase data show nearly 80% of RMS patients treated with Kesimpta (ofatumumab) had no evidence of disease activity (NEDA-3). Novartis. News release. June 27, 2022. Accessed June 29, 2022. https://www.novartis.com/news/media-releases/new-novartis-extension-phase-data-show-nearly-80-rms-patients-treated-kesimpta-ofatumumab-had-no-evidence-disease-activity-neda-3

Mayo Clinic. Multiple sclerosis. Updated January 7, 2022. Accessed June 29, 2022. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269

After 4 years of treatment with ofatumumab, 78.8% of patients with relapsing forms of multiple sclerosis who continuously received ofatumumab achieved NEDA-3 compared to 51.8% of those who switched from teriflunomide to ofatumumab.

Neurology

Ofatumumab Shows Long-Term Improvements in Multiple Sclerosis Disease Activity 

, Paul Feuerstadt, MD, FACG, AGAF, discussed the investigative 

 treatment RBX2660 and how it impacts time to recurrence.

Q: In addition to reducing the recurrence of 

, why is it important to research the time to recurrence?

You know, this is a really important question and one of the controversies over the last, I'll say, 10 to 15 years in the 

 world. What defines a recurrence? Is it 30 days? Is it 60 days? Is it 90 days? Is it 6 months? And when you review the foundational trials, there's a lot of heterogeneity there. The fidaxomicin pivotal trial in the 

 with Tom Louis as the first author from 2011 had a 25-day follow-up. However, all of the microbiota-based live biotherapeutic products, including RBX2660, have an 8-week follow up. So, we really settled on 8 weeks as being that compromise between 1 month and 3 months, really.

But what we've seen through these clinical trials is that the majority of patients that recur, they recur within 4 weeks. And that is very consistent within a number of other trials, both considering RBX2660, but also foundational trials considering fecal microbiota transplant in general. So, within this trial, and within this abstract, what was looked at was the 25th percentile time to recover through a Kaplan-Meier analysis. And what they found was, yes, the majority of recurrences within the phase 3 PUNCH CD3 trial considering RBX2660 head-to-head with placebo, the majority happened within 4 weeks. But the 25th percentile for the placebo arm was 14 days, whereas with RBX2660, it was 30 days. Importantly, that was consistent with the phase 2 trial data Kaplan-Meier analysis of similar structure.

So why is that important? The reason that that's important is when we give a placebo, we're not supplementing anything, so you wouldn't expect colonization resistance to gain any strength from that. And that's what you see 14 days there recurring. Whereas when RBX2660 was used, you see a 30-day 25th percent recurrence. What that speaks to is, yes, there was some supplementation, but it might not have been enough in that small group of patients that recurred. So, what you might hypothesize is by using a second treatment in the future that would further fortify the microbiota and decrease future occurrence.

Q: How did treatment with RBX2660 impact time to recurrence?

So really, the time to recurrence was longer with RBX2660, speaking to the fact that it did fortify the microbiota, and it did supplement some of the deficiencies and it created an environment that was more resistant to recurrence.

Q: How could this finding impact patients’ quality of life and other outcomes?

So, I mean, in general, when you talk about a product like RBX2660, in reducing recurrence that has a significant impact on patient's quality of life. We did a study a couple of years ago that was published in 2020. It was a survey looking at 350 total individuals, and one-third of them had active 

, meaning they had it at the time they completed the survey, and two-thirds of them had a distant history, meaning more than 3 months in the past. And we asked them about the physical symptoms of 

, the abdominal pain, the diarrhea, the fevers, the sweats, the fatigue, and we also ask them about the psychological impact, anxiety, depression, post-traumatic stress disorder. We ask them about the adaptational effect of 

—have they changed how they live their lives? Do they change what they eat? When they eat, how they eat? Do they bring a pack of clothes with them in the event that they have an accident? We ask them about their relational impact. Do they feel comfortable going out and socializing with other people? And finally, the productivity element, which is are they comfortable going to work? Are they able to go to work?

And it turns out for the physical, psychological, adaptational, and relational, more than 50% of patients with active 

 and with a distant history are impacted in a significant way. And for productivity about 51% with active 

 were impacted with active infection, whereas 33% were impacted with a distant history. So, we can see just how all-encompassing this is. And products like RBX2660 can go a long way in reducing recurrence. And I think reducing that impact on these patients’ quality of life, giving them more confidence, less likely to having to adapt in significant ways, be more comfortable going out socially, and honestly earning a living.

You know, this poster is an interesting poster because it validates something that a lot of us in the field have thought previously, which is, A: the majority of recurrence has happened relatively quickly. And B: when you do supplement the microbiota, it can delay the time to recurrence, meaning that it is still working, but certain patients might need more fortification.

Paul Feuerstadt, MD, FACG, AGAF, discussed the investigative C. difficile treatment RBX2660 and how it impacts time to recurrence. 

C. difficile

 Resource Center is a comprehensive resource for clinical news and expert insights on issues related to 

, a bacteria that causes colitis, a serious inflammation of the colon

Novel Treatment Extends Time to Recurrence in Patients With C. Difficile

This webcast discusses opportunities for pharmacists to address the cost of cancer care and enable improved access and outcomes for patients. During the webcast, a panel of experts discusses how pharmacists can help minimize costs associated with cancer therapy, including treatment and clinical practice considerations, as well as more direct financial support that can help ensure access to effective therapies for patients.

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Helping Manage the Cost of Cancer with a Patient Lens: Opportunities for Pharmacists

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. This year alone, more than 150,000 new cases of CRC will be diagnosed, and more than 53,000 people will die from a disease that is not only treatable when discovered early but also preventable.

Yet, 1 in 3 people are not up-to-date with CRC screening. The COVID-19 pandemic impacted screening by causing canceled or delayed colonoscopies and postponed physician visits, which should have included recommendations for CRC screenings. Additional screening barriers include disparities in care for underserved populations, lack of awareness, fear or concerns about the colonoscopy procedure or required prep for it, lack of recommendations by health care providers, or insurance issues.

Delaying regular screenings or follow-up on abnormal results for these reasons or barriers could mean CRC is not detected until later stages. Unfortunately, nearly 63% of newly diagnosed patients have advanced CRC, which requires more aggressive treatment and reduces the associated 5-year survival rate to as low as 14%. In contrast, if detected early, patients with CRC have a 5-year survival rate of 92%.

The Pharmacist’s Role: Earlier Screening is the Key to Prevention

Pharmacists hold a trusted position in their communities and patients see their pharmacists more than twice as often as their primary care providers. In addition, patients visit the pharmacy 35 times a year compared to just 4 visits to see medical providers.

The pharmacists’ role in providing direct patient care and impacting health outcomes holds great potential. Today, pharmacists are perceived as a partner in care and can influence adherence to provider-prescribed treatment plans, such as prescription fulfillment and screenings.

One example is the Kentucky Board of Pharmacy’s 2021 approval of the pharmacy protocol that specifies the criteria and procedures for a pharmacist to provide education and information specific to CRC. As part of the protocol, when appropriate, a pharmacist may initiate noninvasive, stool-based CRC screening with a customer by distributing a take-home fecal immunochemical test (FIT) or stool DNA test (e.g., sDNA-FIT)—making it even easier for patients to follow their health care providers’ recommended screening guidelines.

These patients can now take care of their CRC screening at their local pharmacy—the same place they go for a flu shot, COVID-19 vaccination, or regular prescriptions. The protocol was approved following advocacy efforts to remove barriers to screening in Kentucky by the Colon Cancer Prevention Project and Fight Colorectal Cancer (Fight CRC).

CRC is treatable and preventable when caught early. Providing people with additional options to get screened saves more lives, a position that resonates with the American Association of Colleges of Pharmacy’s Oath of the Pharmacist vow. Removing barriers to access and opening paths to prevention and detection align with the pharmacists’ promise to advance health equity and embrace and advocate for changes that improve patient care.

Most CRC develops from precursor polyps, the most common neoplastic finding in colonoscopy. Colonoscopy has a 3.5% false-negative rate for detecting CRC, but its significant advantage is the ability to remove premalignant lesions discovered during the screening or surveillance procedure.

The potential for these polyps to become malignant correlates with the polyp's type, size, and degree of dysplasia. Advanced adenomas (AA) are considered the most concerning and high-risk type of polyp. Secondary prevention of CRC involves screening at-risk populations to detect and remove early-stage cancers and adenomatous polyps.

The American Cancer Society and the United States Preventative Task Force (USPSTF) recommend secondary prevention in average-risk individuals, including beginning screening at age 45. While the USPSTF does not specify the advantages of any screening strategy, colonoscopy remains the gold standard for CRC screening and detecting colorectal lesions. Despite this, compliance with colonoscopy is not optimal due to discomfort and unpleasant preparation procedures.

Limitations include the risk of complications, cost, and access. By contrast, the ideal CRC screening method would be low-cost and noninvasive, with good patient acceptance and high sensitivity and specificity values.

FIT, which detects hemoglobin in the stool, has been used with some success. FIT has a low sensitivity for colon adenomas (66–80% sensitivity for CRC) and poor precursor lesion detection rates (only 10–28% for AA). But even with an excellent specificity (93–95%), the aggregate metrics limit its effectiveness.

It is well known that not all colorectal adenomas will progress to CRC. Increasing the sensitivity for high‐risk adenomas can raise the detection rates for these lesions. Therefore, it is imperative to explore alternative or complementary strategies with the potential to improve CRC screening performance, especially for the detection of cancers at their early stages and AA.

Identifying novel protein biomarker panels with higher sensitivities for high‐risk adenomas and CRC than FIT will improve current screening strategies. These additional biomarkers could aid in enhancing the sensitivity for early detection of CRC. The development of tests performed on stool samples that see indirect signs of CRC, such as occult blood or genetic and epigenetic alterations related to the presence of CRC, has been achieved with good results.

One attractive category of molecules considered for stool-based CRC screening is RNA. RNA-based biomarkers can be measured in small sample volumes with simple economic assays. Combining specific stool‐based RNA biomarkers outperform hemoglobin and DNA in detecting molecularly defined high‐risk adenomas.

Host mRNA has also been investigated in stool as a potential biomarker. In one study, a multitargeted stool RNA (mt-sRNA) assay combined 8 stool-derived eukaryotic RNA (seRNA) biomarkers, patient demographic information (smoking status), and a FIT to detect colorectal neoplasia.

In stool samples using a robust predictive model, the test attained a 95% sensitivity for CRC, 62% sensitivity for AA, 25% sensitivity for other non-AA, 80% specificity for hyperplastic polyps, and 85% specificity for no findings on a colonoscopy. This study demonstrated that specific RNA expression alterations in colon tissue prove valuable in early CRC diagnosis and potentially prognosis prediction and targeted therapy. More recently, a multitarget mRNA assay demonstrated a significant strengthening of both sensitivity and specificity for CRC detection.

In summary, the cost-benefit of such new methods for the health care system may encourage changes to current screening recommendations. The high cost of CRC treatment, particularly for more advanced diseases, is considered to improve the cost-effectiveness of CRC screening. Furthermore, higher threshold costs for a biomarker test that could significantly increase the sensitivity of AA detection while maintaining reasonable specificity would likely be cost-effective relative to currently available noninvasive tests.

1. Barnell EK, Kang Y, Barnell AR, et al. Multitarget stool RNA test for noninvasive detection of colorectal neoplasias in a multicenter, prospective, and retrospective cohort. Clin Transl Gastroenterol. 2021;12(5):e0036.

Joseph Moose, P., & Ashley Branham, P. (2014). Pharmacists as Influencers of Patient Adherence. Pharmacy Times Oncology Edition, 1(5). https://www.pharmacytimes.com/view/pharmacists-as-influencers-of-patient-adherence-[Accessed 16 June 2022].

"Pharmacists' role in primary care set to grow

.” [online] MM+M - Medical Marketing and Media. https://www.mmm-online.com/home/channel/pharmacists-[Accessed 16 June 2022].

“Pharmacists Want More Time with Patients.”

 (n.d.). Drug Topics. https://www.drugtopics.com/view/pharmacists-want-more-time-patients

Simon K. Colorectal cancer development and advances in screening. 

Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. 

Welch HG, Robertson DJ. Colorectal cancer on the decline--why screening can’t explain it all. 

Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. 

Westwood C, Lee T, McSherry R, Bettany-Saltikov J, Catlow J. Decision making in the management of adults with malignant colorectal polyps: An exploration of the experiences of patients and clinicians. 

Swinton NW Sr, Nahra KS, Khazei AM, Scherer WP. The evolution of colorectal cancer. 

Pohl H, Srivastava A, Bensen SP, et al. Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study. 

Nearly 63% of newly diagnosed patients have advanced colorectal cancer, which requires more aggressive treatment and reduces the associated 5-year survival rate.

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