Wall Street apparently wasn't much pleased with the boxed warning on Verastem Inc.'s first approved product, trimming shares (NASDAQ:VSTM) by 19.6 percent, or $1.74, so they closed Tuesday at $7.15, even though analysts pointed out that the side effects with Copiktra (duvelisib) can be handled by doctors.
"As we have previously noted, according to the study investigators these adverse events are similar to those found with other chronic lymphocytic leukemia [CLL] therapies and can be managed through prophylactic treatments using antibiotics and granulocyte-colony stimulating factor," H.C. Wainwright analyst Swayampakula Ramakanth wrote in a report.
Raymond James analyst Reni Benjamin liked the approval, too. "With the commercialization of duvelisib about to be underway, the potential to generate $266 million at peak from all three indications, and a cash position of $138 million (pro forma), we continue to recommend Verastem to risk-tolerant investors," he said in his report.
About two weeks ahead of the Oct. 5 PDUFA date, Needham, Mass-based Verastem won FDA clearance for Copiktra in adults with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) after at least two prior therapies. An oral inhibitor of phosphoinositide 3-kinase (PI3K), Copiktra is the first approved dual inhibitor of PI3K-delta and PI3K-gamma, enzymes that help malignant B cells grow.
The drug also won accelerated approval, based on overall response rate, for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Further approval in FL could depend on what confirmatory trials show, the company said.
Copiktra bears a boxed warning for fatal and/or serious toxicities that include infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem is putting in place an informational risk evaluation and mitigation strategy (REMS) to provide appropriate dosing and safety guidance for doctors. The drug is also linked to adverse reactions that may call for reducing the dose, delaying treatment, or quitting altogether. Warnings and precautions mention the four risks as well as hepatotoxicity, neutropenia and embryo-fetal toxicity. The most common adverse reactions – reported in greater than or equal to 20 percent of patients – were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.
Benjamin called the drug's safety in line with, if not better than, other drugs in its class. "By way of comparison, idelalisib [Zydelig, Gilead Sciences Inc.], another PI3K inhibitor approved for CLL, SLL and FL, received a black-box warning describing hepatotoxicity in 16 percent to 18 percent of treated patients, as well as comparable rates of fatal and/or serious infections, diarrhea and colitis, and pneumonitis," he said. "Ultimately, we believe the combination of hepatotoxicity and the other side effects led to the demise of idelalisib combination therapies, a strategy that may now be pursuable with Copiktra."
Bayer AG, of Leverkusen, Germany, has won marketing clearance for FL treatment Aliqopa (copanlisib).
Daniel Paterson, principal financial officer, said during a conference call with investors that the company has "prepared all the [REMS] materials, be it hard-copy things, things we'll be distributing to the societies, [or] the website, just to make sure we have the material out there and even down to [the fact that] there's going to be patient information wallet cards. If a patient shows up at the emergency room, for example, and is on the drug, they've got the information in the wallet card," he said, adding that "we did learn a little, I think, from the idelalisib launch, and I think it's a combination of just being very forthright in our education but also understanding that the market's evolved since then."
Earlier lines of treatment next?
Copiktra was tested in late- and midstage extension trials, including Duo, a randomized, phase III monotherapy study in CLL/SLL, and Dynamo, a phase II monotherapy experiment in patients with refractory indolent non-Hodgkin's lymphoma. Both achieved their primary endpoints.
George Zavoico, analyst with B. Riley FBR Inc., asked whether serious adverse events (AEs) with Copiktra might lessen as time passes. "Yes – I mean, one can hope," Paterson said. "I think it is important. You hit on an important point, [which is that] when we talk to the physicians who've used the drug, I think they get more comfortable the more experience they have. And we've not done an analysis of patients accrued later in the program vs. earlier, necessarily, but I think it's just natural as physicians get more comfortable and know what to expect, they do a better job of managing side effects. Just look at physicians overall and their comfort with immuno-oncology agents and the spectrum of AEs that they hadn't seen before when they used traditional chemotherapy."
Joseph Lobacki, chief commercial officer, said Verastem has "been working, over the past few months, to build the team to launch Copiktra. In fact, just a little over a week ago, we had the whole field team here in Boston to continue to prepare for that launch, in terms of training and messaging and just looking at the data. We've got a team of 50 sales representatives in the field who are ready to go. They have eight regional managers and two vice presidents leading them. We've got a great marketing and market research team that has provided information on the marketplace to help guide the sales team forward, and we have an excellent medical and science liaison group that's been out working with physicians over the past several months, just finding out about the market, educating them on the duvelisib data. I think we're ready to go."
Copiktra bears a list price of $11,800 per month, and is given twice daily in a 25-mg dose.
Near the start of September, Verastem disclosed that the first patient was given Copiktra in a multicenter phase I/II trial at the Dana-Farber/Harvard Cancer Center testing the drug in combination with Venclexta (venetoclax, Abbvie Inc. and Roche Holding AG) in CLL/SLL. Oppenheimer analyst Leah Rush Cann noted that if the experiment can confirm the combo is well-tolerated and improves the complete response rate over either agent alone, the finding "could lead to the use of duvelisib in earlier lines of treatment than currently being evaluated," she wrote in a report. "While preclinical data support this combination, we are not adjusting our outlook at this time due to the timing and phase of this new study."